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TWI727173B - Use of anti-tumor effect enhancers with novel biphenyl compounds - Google Patents

Use of anti-tumor effect enhancers with novel biphenyl compounds Download PDF

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Publication number
TWI727173B
TWI727173B TW107117996A TW107117996A TWI727173B TW I727173 B TWI727173 B TW I727173B TW 107117996 A TW107117996 A TW 107117996A TW 107117996 A TW107117996 A TW 107117996A TW I727173 B TWI727173 B TW I727173B
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TW
Taiwan
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alkyl
substituent
substituted
same
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TW107117996A
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Chinese (zh)
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TW201900162A (en
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長田亞希子
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日商大鵬藥品工業股份有限公司
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/42—Oxazoles
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Abstract

一種併用投予聯苯化合物或其鹽、與其他抗腫瘤劑之抗腫瘤劑，前述聯苯化合物係通式(I)[式中，環A、環B、R1~R6、l、m、n具有如在說明書中所定義之意思]表示且具有LSD1抑制活性。

Figure 107117996-A0101-11-0001-2
An anti-tumor agent for co-administering a biphenyl compound or its salt with other anti-tumor agents. The aforementioned biphenyl compound is of general formula (I) [wherein, ring A, ring B, R1~R6, l, m, n It has the meaning defined in the specification] and has LSD1 inhibitory activity.
Figure 107117996-A0101-11-0001-2

Description

使用有新穎聯苯化合物之抗腫瘤效果增強劑Use of anti-tumor effect enhancers with novel biphenyl compounds

本發明有關於一種組合聯苯化合物或其鹽、與其他抗腫瘤劑而成之抗腫瘤劑，以及關於一種其他抗腫瘤劑之抗腫瘤效果增強劑。The present invention relates to an anti-tumor agent formed by combining a biphenyl compound or its salt with other anti-tumor agents, and to an anti-tumor effect enhancer of other anti-tumor agents.

藉由甲基化組織蛋白進行的修飾係控制基因表現的表觀遺傳(epigenetic)機制之一，該修飾係進行細胞之維持、增殖、分化等各種作用之控制。One of the epigenetic mechanisms that control gene expression by a modified system of methylated tissue protein, the modified system controls various functions such as cell maintenance, proliferation, and differentiation.

控制該等組織蛋白之甲基化修飾的酵素之一--LSD1(KDM1A)，係與FAD(黃素腺嘌呤二核苷酸)依存之組織蛋白去甲基化酵素，且主要是進行組織蛋白H3之第4號的離胺酸殘基(K4)及第9號的離胺酸殘基(K9)之去甲基化的酵素(非專利文獻1)。目前認為LSD1藉由發揮其機能而正或負調節各種基因的轉錄，而在各正常組織中控制幹細胞的自我更新、細胞之分化等。One of the enzymes that control the methylation modification of these tissue proteins-LSD1 (KDM1A), is a tissue protein demethylation enzyme dependent on FAD (flavin adenine dinucleotide), and is mainly used for tissue protein Enzymes that demethylate the 4th lysine residue (K4) and the 9th lysine residue (K9) of H3 (Non-Patent Document 1). At present, it is believed that LSD1 can positively or negatively regulate the transcription of various genes by exerting its function, and control the self-renewal of stem cells and the differentiation of cells in normal tissues.

一般而言，目前認為細胞自我更新能或分化的異常係與細胞之癌化有關，因此，對此作用扮演重要角色的LSD1，其控制異常會有成為細胞癌化的原因之可能性。實際上，在各種類型的實質癌或血液癌中，LSD1的過量表現或其與預後之關聯已有很多報告(非專利文獻2)。又，有報告指出在若干源自癌種的細胞株或非臨床模式中藉由抑制LSD1而造成細胞分化誘導、增殖抑制、於活體內(in vivo)的抗腫瘤效果(非專利文獻3、4)，而強烈暗示LSD1係癌症治療的重要標的分子之一。該等與LSD1相關的癌種，例如小細胞肺癌(SCLC)或急性骨髄性白血病(AML)係生存期間極短的癌種，且利用既存的治療方法服無法獲得滿足的治療效果。Generally speaking, it is currently believed that the abnormal lineage of cell self-renewal or differentiation is related to the canceration of cells. Therefore, LSD1, which plays an important role in this role, may have the possibility of its abnormal control as the cause of canceration of cells. In fact, there have been many reports on the overexpression of LSD1 or its relationship with prognosis in various types of parenchymal cancer or hematological cancer (Non-Patent Document 2). In addition, there are reports that the inhibition of LSD1 in several cancer-derived cell lines or non-clinical models leads to cell differentiation induction, proliferation inhibition, and anti-tumor effects in vivo (Non-Patent Documents 3, 4). ), and strongly suggests that LSD1 is one of the important target molecules for cancer treatment. These LSD1 related cancers, such as small cell lung cancer (SCLC) or acute bone leukemia (AML), are cancers with a very short survival period and cannot achieve satisfactory therapeutic effects by using existing treatment methods.

從以上來看，對於目前不存在治療法之難治性癌症，可期待抑制LSD1之藥劑能提供一種基於新機制的有效治療手段。From the above point of view, for refractory cancers for which no treatment currently exists, it can be expected that agents that inhibit LSD1 can provide an effective treatment method based on a new mechanism.

除此之外，有鑑於LSD1與神經細胞之編程(program)或機能相關，有報告指出LSD1可成為對阿茲海默症、杭丁頓舞蹈症、瑞特氏症候群等之腦神經疾病(非專利文獻2)、被暗示與LSD1機能相關的疱疹病毒感染症(非專利文獻5)或鐮形血球貧血症等(非專利文獻6)癌症以外之疾病的治療標的。In addition, in view of the fact that LSD1 is related to the programming or function of nerve cells, there are reports that LSD1 can be used to treat Alzheimer’s disease, Huntington’s disease, Reiter’s syndrome and other cranial nerve diseases (non- Patent Document 2), herpes virus infection (Non-Patent Document 5) or sickle cell anemia (Non-Patent Document 6) suggested to be related to the function of LSD1 (Non-Patent Document 6) is a therapeutic target for diseases other than cancer.

已有數個報告指出藉由LSD1抑制劑與其他抗腫瘤劑之組合所產生的抗腫瘤效果。例如，已有報告指出，藉由LSD1抑制劑之SP2509與組織蛋白去乙醯酵素抑制劑之帕比司他(panobinostat)之組合所產生之對急性骨髄性白血病的抗腫瘤效果(非專利文獻7)。又，已有報告指出，藉由LSD1抑制劑之INCB059872與全反式維甲酸(ATRA)之組合所產生之對急性骨髄性白血病的抗腫瘤效果(非專利文獻8)。Several reports have pointed out the anti-tumor effects produced by the combination of LSD1 inhibitors and other anti-tumor agents. For example, it has been reported that the combination of SP2509, an LSD1 inhibitor, and panobinostat, an inhibitor of tissue protein deacetylase, has an anti-tumor effect on acute bone marrow leukemia (Non-Patent Document 7). ). In addition, it has been reported that the combination of INCB059872, an LSD1 inhibitor, and all-trans retinoic acid (ATRA) has an anti-tumor effect on acute bone marrow leukemia (Non-Patent Document 8).

先行技術文獻非專利文獻非專利文獻1：Biochim. Biophys. Acta, 1829(10), P.981-986(2013)非專利文獻2：Epigenomics,7(4), P.609-626(2015)非專利文獻3：Cancer Cell,21(4), P.473-487(2012)非專利文獻4：Cancer Cell,28(1), P.57-69(2015)非專利文獻5：Sci. Transl. Med., 6(265), 265ra169(2014)非專利文獻6：Nat. Med., 19(3), P.291-294(2013)非專利文獻7：Leukemia, 28(11), P.2155- 2164(2014)非專利文獻8：Cancer　Res.,　74(14　Suppl)Abstract　4696(2016)Prior Art Literature Non-Patent Literature Non-Patent Literature 1: Biochim. Biophys. Acta, 1829(10), P.981-986 (2013) Non-Patent Literature 2: Epigenomics, 7(4), P.609-626 (2015) Non-Patent Document 3: Cancer Cell, 21(4), P.473-487 (2012) Non-Patent Document 4: Cancer Cell, 28(1), P.57-69 (2015) Non-Patent Document 5: Sci. Transl Med., 6(265), 265ra169 (2014) Non-Patent Document 6: Nat. Med., 19(3), P.291-294 (2013) Non-Patent Document 7: Leukemia, 28(11), P. 2155-2164 (2014) Non-Patent Document 8: Cancer　Res., 　74(14　Suppl)Abstract　4696 (2016)

發明欲解決之課題本發明之課題在於提供一種增強抗腫瘤效果的方法，前述抗腫瘤效果係透過強力抑制LSD1之化合物或其鹽所產生。Problem to be Solved by the Invention The problem of the present invention is to provide a method for enhancing the anti-tumor effect. The anti-tumor effect is produced by a compound or its salt that strongly inhibits LSD1.

用以解決課題之手段本案發明人等為解決前述課題而一再精心探討，結果發現，下述通式(I)表示的化合物或其鹽在與其他具有抗腫瘤效果之化合物(其他抗腫瘤劑)併用時，具有優易的抗腫瘤效果之增強作用，進而完成本發明。Means to Solve the Problem The inventors of this case have repeatedly studied to solve the aforementioned problem and found that the compound represented by the following general formula (I) or its salt is compatible with other compounds having antitumor effects (other antitumor agents) When used in combination, it has an excellent and easy enhancing effect of anti-tumor effect, thereby completing the present invention.

亦即，本發明提供以下態樣：　項1. 一種抗腫瘤劑，特徵在於將以下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑併用投予：That is, the present invention provides the following aspects: "Item 1. An antitumor agent characterized in that a biphenyl compound represented by the following general formula (I) or a salt thereof is administered in combination with other antitumor agents:

[化學式1]

Figure 02_image001
[Chemical formula 1]
Figure 02_image001

[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group may also have a C3-C7 cycloalkyl group with a hydroxyl group as a substituent, or a (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項2.如項1記載之抗腫瘤劑，其中聯苯化合物在通式(I)中滿足下述條件：環A為吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基(azepanyl group)、二吖
Figure 107117996-A0101-12-0012-002
基(diazepanyl group)、Item 2. The antitumor agent according to Item 1, wherein the biphenyl compound satisfies the following conditions in the general formula (I): Ring A is pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base (azepanyl group), two acridine
Figure 107117996-A0101-12-0012-002
Base (diazepanyl group),

[化學式2]

Figure 02_image003
[Chemical formula 2]
Figure 02_image003

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，環B為苯基、萘基、吡啶基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、吲哚啉基、2-側氧基-吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹唑啉基、喹噁啉基、呔嗪基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基(dihydrobenzoxazinyl)、苯并二噁

Figure 107117996-A0101-12-0054-2
基 (benzodioxolyl)、二氫苯并二噁嗪基(dihydrobenzodioxinyl)，或2-側氧基-2,3-二氫苯并[d]噻唑基，R1為硝基或氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基(當R3存在有複數個時，該等R3可相同亦可相異)，R4為氟原子、氯原子、溴原子、碘原子、硝基、氰基、羧基、甲基、乙基、正丙基、異丙基、第三丁基、二氟甲基、三氟甲基、氟乙基、胺基乙基、羥基甲基、羥基乙基、羥基丙基、羥基二甲基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、羧基甲基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、乙醯基胺基乙基、甲氧基乙基、羥基環丙基甲基、羥基環丙基乙基、羥基環丁基甲基、甲基羰基氧基乙基、異丁烯基、甲氧基、羥基丙氧基、環丙基、羥基甲基環丙基、甲氧基甲基環丙基、羥基環丙基環丙基、苯基胺甲醯基環丙基、苯甲基氧基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基(當R4存在有複數個時，該等R4可相同亦可相異)，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，n表示0~3之整數。當n為2~3時，2~3個R4可相同亦可相異。, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B is phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indolinyl, 2- Pendant oxy-indolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, Quinazolinyl, quinoxalinyl, oxazinyl, 2-side oxy-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzene Dihydrobenzoxazinyl, benzodioxin
Figure 107117996-A0101-12-0054-2
Group (benzodioxolyl), dihydrobenzodioxinyl (dihydrobenzodioxinyl), or 2-side oxy-2,3-dihydrobenzo[d]thiazolyl, R1 is nitro or cyano, R2 is fluorine atom , The R2 exists in the ortho position relative to R1 on the phenyl group, and R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, a cyclobutylamino group, or a methyl group. Group (when there are plural R3, these R3 may be the same or different), R4 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, a normal Propyl, isopropyl, tertiary butyl, difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, Hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxymethyl, carbamate methyl, methyl carbamate, dimethyl carbamate, acetyl Aminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutenyl, methoxy, hydroxypropoxy , Cyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, phenylaminomethylcyclopropyl, benzyloxy, dimethylamino , Carbamate, methyl carbamate, or dimethyl carbamate (when there are more than one R4, these R4 can be the same or different), R5 and R6 are the same or different, which means A hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1-C6 alkyl group. At least 1 is a hydrogen atom, and n represents an integer from 0 to 3. When n is 2~3, 2~3 R4 can be the same or different.

項3.如項1或2記載之抗腫瘤劑，其中聯苯化合物是選自以下之(1)~(7)者：(1)4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈(2)4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈(3)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈-異構物-B(4)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-B(5)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X(6)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X(7)5’-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-XItem 3. The antitumor agent according to Item 1 or 2, wherein the biphenyl compound is selected from the group consisting of (1) to (7): (1) 4-[5-[(3S)-3-aminopyrrole Pyridin-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile(2)4-[5 -[(3-Internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl- Propyl)phenyl]phenyl)-2-fluoro-benzonitrile(3)5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]hepta Alkyl-7-carbonyl)-2``,3-difluoro-4''-(2-hydroxy-2-methylpropyl)-[1,1':2',1''-terphenyl] -4-carbonitrile-isomer-B(4)5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl) -2'-(6,7-Difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3 -Fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B(5)5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo [2.2.1]Heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2 ,3]Triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X(6)5'-((1S,2S,4R)- rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl) )-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X(7 )5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(6,7- Difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- Biphenyl]-4-carbonitrile-isomer-X

項4. 如項1~3中任1項記載之抗腫瘤劑，其中其他抗腫瘤劑選自於が代謝拮抗劑、抗腫瘤性抗生素、分子標的藥、鉑系藥劑、及植物生物鹼藥劑中之至少1種以上。Item 4. The antitumor agent according to any one of items 1 to 3, wherein the other antitumor agent is selected from metabolic antagonists, antitumor antibiotics, molecular target drugs, platinum-based drugs, and plant alkaloid drugs At least one of them.

項5. 如項1~3中任1項記載之抗腫瘤劑，其中其他抗腫瘤劑為選自於阿糖胞苷、氮雜胞苷、地西他濱、鳥地西他濱、道諾黴素、維A酸(ATRA)、RG7388、卡鉑、順鉑、紫杉醇、愛萊諾迪肯(SN-38)、及依託泊苷中之至少1種以上。Item 5. The anti-tumor agent according to any one of items 1 to 3, wherein the other anti-tumor agent is selected from the group consisting of cytarabine, azacytidine, decitabine, guandecitabine, daunor At least one or more of tetracycline, tretinoin (ATRA), RG7388, carboplatin, cisplatin, paclitaxel, elenodic (SN-38), and etoposide.

第6項. 一種其他抗腫瘤劑之抗腫瘤效果增強劑，係以下述通式(I)表示的聯苯化合物或其鹽做為有效成分化合物或其鹽：Item 6. An anti-tumor effect enhancer of other anti-tumor agents, which uses the biphenyl compound represented by the following general formula (I) or its salt as an active ingredient compound or its salt:

[化學式3]

Figure 02_image001
[Chemical formula 3]
Figure 02_image001

[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項7.一種抗腫瘤劑，含有用以治療已投予其他抗腫瘤劑之癌症患者的聯苯化合物或其鹽，聯苯化合物為下述通式(I)表示的化合物：Item 7. An antitumor agent containing a biphenyl compound or a salt thereof for treating cancer patients who have been administered other antitumor agents, the biphenyl compound being a compound represented by the following general formula (I):

[化學式4]

Figure 02_image001
[Chemical formula 4]
Figure 02_image001

[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項8.一種抗腫瘤劑，係組合聯苯化合物或其鹽、與其他抗腫瘤劑而成者，聯苯化合物為下述通式(I)表示的化合物：Item 8. An antitumor agent, which is a combination of a biphenyl compound or a salt thereof with other antitumor agents, and the biphenyl compound is a compound represented by the following general formula (I):

[化學式5]

Figure 02_image001
[Chemical formula 5]
Figure 02_image001

[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

第9項. 一種用於預防及/或治療腫瘤之醫藥組成物，含有以下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑：[化學式6]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 9. A pharmaceutical composition for the prevention and/or treatment of tumors, containing a biphenyl compound represented by the following general formula (I) or a salt thereof, and other antitumor agents: [Chemical formula 6]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項10.一種以下述通式(I)表示的聯苯化合物或其鹽，係用以增強其他抗腫瘤劑之抗腫瘤效果者：[化學式7]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 10. A biphenyl compound represented by the following general formula (I) or a salt thereof, which is used to enhance the antitumor effect of other antitumor agents: [Chemical formula 7]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項11.一種以下述通式(I)表示的聯苯化合物或其鹽之用途，係用以增強其他抗腫瘤劑之抗腫瘤效果者： [化學式8]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 11. A use of a biphenyl compound represented by the following general formula (I) or a salt thereof to enhance the anti-tumor effect of other anti-tumor agents: [Chemical formula 8]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項12.一種以下述通式(I)表示的聯苯化合物或其鹽之用途，係用以製造其他抗腫瘤劑之抗腫瘤效果增強劑者： [化學式9]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 12. A use of a biphenyl compound represented by the following general formula (I) or a salt thereof to produce an antitumor effect enhancer of other antitumor agents: [Chemical formula 9]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

第13項. 一種腫瘤之預防及/或治療方法，含有將下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑組合且對患者投予對治療及/或預防有效之量的步驟： [化學式10]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 13. A method for the prevention and/or treatment of tumors, which contains a biphenyl compound represented by the following general formula (I) or a salt thereof in combination with other antitumor agents and is effective for treatment and/or prevention when administered to a patient The amount of steps: [Chemical formula 10]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項14.一種腫瘤之預防及/或治療方法，含有對已投予其他抗腫瘤劑之癌症患者投予對治療及/或預防有效之量之下述通式(I)表示的聯苯化合物或其鹽的步驟：[化學式11]

Figure 02_image005
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 14. A method for the prevention and/or treatment of tumors, comprising administering to a cancer patient who has been administered other antitumor agents a therapeutically and/or preventively effective amount of a biphenyl compound represented by the following general formula (I) or The steps of its salt: [Chemical formula 11]
Figure 02_image005
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

第15項. 一種抗腫瘤效果增強方法，含有對已投予其他抗腫瘤劑之癌症患者投予對治療及/或預防有效之量之下述通式(I)表示的聯苯化合物或其鹽的步驟：[化學式12]

Figure 02_image001
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 15. A method for enhancing antitumor effect, comprising administering to a cancer patient who has been administered other antitumor agents a therapeutically and/or preventively effective amount of a biphenyl compound represented by the following general formula (I) or a salt thereof The steps: [Chemical formula 12]
Figure 02_image001
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

項16.一種含有聯苯化合物或其鹽與其他抗腫瘤劑之製品，其係作為一組合製劑，且該組合製劑在用來預防及/或治療腫瘤時，是同時、逐次、或隔著間隔來使用，聯苯化合物為下述通式(I)表示的聯苯化合物：[化學式13]

Figure 02_image005
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 16. A product containing a biphenyl compound or its salt and other anti-tumor agents, which is used as a combined preparation, and when the combined preparation is used to prevent and/or treat tumors, it is used simultaneously, successively, or at intervals For use, the biphenyl compound is a biphenyl compound represented by the following general formula (I): [Chemical formula 13]
Figure 02_image005
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

第17項. 一種以下述通式(I)表示的聯苯化合物或其鹽與其他抗腫瘤劑之組合：[化學式14]

Figure 02_image005
[式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異。R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數。當l為2時，2個R2可相同亦可相異。當m為2時，2個R3可相同亦可相異。當n為2~5時，2~5個R4可相同亦可相異。]。Item 17. A combination of a biphenyl compound represented by the following general formula (I) or a salt thereof and other antitumor agents: [Chemical formula 14]
Figure 02_image005
[In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents A halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered unsaturated hydrocarbon group may also have as a substituent C1-C6 alkyl or monocyclic and 5- to 10-membered unsaturated hydrocarbon group amine methionyl, (C2-C7 acyl)oxy group, or C1-C6 alkyl group or C2 as a substituent The amino group of -C7 acyl group, the C3-C7 cycloalkyl group which may have a hydroxyl group as a substituent, or the (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are a plurality of such substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together form a pendant oxy group or a thioketone group. When R5 and R6 are the same or different, they represent a hydrogen atom or a C1- In the case of a C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, the two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4 can be the same or different. ].

發明效果若依據本發明，將可在抑制副作用發病之同時，進行發揮出優異抗腫瘤效果之癌症治療。Effects of the Invention According to the present invention, cancer treatment with excellent anti-tumor effects can be performed while suppressing the onset of side effects.

用以實施發明之型態在本發明中，與其他抗腫瘤劑發揮優異協同作用之LSD1抑制劑為下述通式(I)表示的聯苯化合物或其鹽。Modes for Carrying Out the Invention In the present invention, the LSD1 inhibitor that exerts an excellent synergistic effect with other antitumor agents is a biphenyl compound represented by the following general formula (I) or a salt thereof.

[化學式15]

Figure 02_image001
(式中，環A、環B、R1~R6、l、m、n如前述定義。)[Chemical formula 15]
Figure 02_image001
(In the formula, ring A, ring B, R1~R6, l, m, and n are as defined above.)

於本案說明書中，當未另行規定時，「取代基」可舉例如：鹵素原子、羥基、氰基、硝基、烷基、羥基烷基、鹵代烷基、環烷基、羥基環烷基、環烷基-烷基、芳烷基、烯基、炔基、烷氧基、鹵代烷氧基、環烷氧基、環烷基-烷氧基、不飽和烴環-烷氧基、烷基硫基、環烷基-烷基硫基、胺基、單或二烷基胺基、環烷基胺基、環烷基-烷基胺基、醯基、醯基氧基、側氧基、羧基、烷氧基羰基、芳烷基氧基羰基、亦可具有作為取代基之不飽和烴環基的胺甲醯基、飽和或不飽和雜環基、不飽和烴環基(芳香族烴基等)、飽和雜環氧基等，且當前述取代基係存在時，其個數典型為1個、2個或3個。In the specification of this case, when not otherwise specified, "substituents" can include, for example, halogen atoms, hydroxyl groups, cyano groups, nitro groups, alkyl groups, hydroxyalkyl groups, halogenated alkyl groups, cycloalkyl groups, hydroxycycloalkyl groups, and cyclic groups. Alkyl-alkyl, aralkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyl-alkoxy, unsaturated hydrocarbon ring-alkoxy, alkylthio , Cycloalkyl-alkylthio, amino, mono- or dialkylamino, cycloalkylamino, cycloalkyl-alkylamino, acyl, acyloxy, pendant oxy, carboxy, An alkoxycarbonyl group, an aralkyloxycarbonyl group, an aminomethanyl group which may also have an unsaturated hydrocarbon ring group as a substituent, a saturated or unsaturated heterocyclic group, an unsaturated hydrocarbon ring group (aromatic hydrocarbon group, etc.), Saturated heterocyclic oxy group, etc., and when the aforementioned substituent system is present, the number thereof is typically 1, 2, or 3.

於本案說明書中「鹵素原子」可列舉：氟原子、氯原子、溴原子、碘原子等，且較佳為氟原子、氯原子、溴原子或碘原子，且更佳為氟原子或氯原子。In the specification of the present case, the "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., and is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and more preferably a fluorine atom or a chlorine atom.

於本案說明書中「烷基」可為直鏈狀或支鏈狀之任一者，且可舉例如：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、第三戊基、正己基等之C1-C6烷基。In the specification of this case, the "alkyl" can be either linear or branched, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and C1-C6 alkyl groups such as dibutyl, tertiary butyl, n-pentyl, isopentyl, tertiary pentyl, and n-hexyl.

於本案說明書中，「羥基烷基」可舉例如：具有至少1個(例如1個或2個)羥基的，前述所列舉的烷基等。具體而言，包含羥基甲基、2-羥基乙基、1-羥基乙基、3-羥基丙基、2-羥基丙基、1-甲基-2-羥基乙基、4-羥基丁基、2,2-二甲基-2-羥基乙基、5-羥基戊基、3,3-二甲基-3-羥基丙基、6-羥基己基、二羥基甲基、1,2-二羥基乙基、2,3-二羥基丙基、3,4-二羥基丁基、4,5-二羥基戊基、5,6-二羥基己基等，且較佳為具有1個羥基的羥基烷基。In the specification of the present case, the "hydroxyalkyl group" includes, for example, those having at least one (for example, one or two) hydroxyl groups, the aforementioned alkyl groups, and the like. Specifically, it contains hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl, 4-hydroxybutyl, 2,2-Dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 3,3-dimethyl-3-hydroxypropyl, 6-hydroxyhexyl, dihydroxymethyl, 1,2-dihydroxy Ethyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 4,5-dihydroxypentyl, 5,6-dihydroxyhexyl, etc., and preferably a hydroxyalkane having one hydroxyl group base.

於本案說明書中「鹵代烷基」係指具有1~13個鹵素原子之碳數1至6的直鏈狀或支鏈狀烷基(鹵代C1-C6烷基)，可舉例如：氟甲基、二氟甲基、三氟甲基、三氯甲基、氟乙基、1,1,1-三氟乙基、單氟-正丙基、全氟-正丙基、全氟異丙基等之鹵代C1-C6烷基，且較佳可列舉鹵代C1-C4烷基，且更佳為具有1~7個鹵素原子之鹵代C1-C4烷基。In the specification of this case, "haloalkyl" refers to a linear or branched alkyl with 1 to 13 halogen atoms and a carbon number of 1 to 6 (halogenated C1-C6 alkyl), for example: fluoromethyl , Difluoromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl, perfluoro-n-propyl, perfluoroisopropyl Such as halogenated C1-C6 alkyl groups, preferably halogenated C1-C4 alkyl groups, and more preferably halogenated C1-C4 alkyl groups having 1 to 7 halogen atoms.

於本案說明書中「環烷基」之具體例可列舉；環丙基、環丁基、環戊基、環己基、環庚基等之C3-C7環烷基。Specific examples of "cycloalkyl" in the specification of this case include C3-C7 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

於本案說明書中「羥基環烷基」可舉例如：具有至少1個(例如1個或2個)羥基的，前述所列舉的C3-C7環烷基等。具體可列舉：1-羥基環丙基、2-羥基環丙基、1-羥基環丁基、3-羥基環丁基、1-羥基環戊基、3,4-二羥基環戊基、1-羥基環己基、4-羥基環己基、1-羥基環庚基等，且較佳可列舉：具有1個羥基的羥基環烷基。In the specification of the present case, the "hydroxycycloalkyl group" includes, for example, those having at least one (for example, one or two) hydroxyl groups, the C3-C7 cycloalkyl groups listed above, and the like. Specific examples include: 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 1-hydroxycyclobutyl, 3-hydroxycyclobutyl, 1-hydroxycyclopentyl, 3,4-dihydroxycyclopentyl, 1 -Hydroxycyclohexyl, 4-hydroxycyclohexyl, 1-hydroxycycloheptyl, etc., and preferably include: hydroxycycloalkyl having one hydroxy group.

於本案說明書中「環烷基-烷基」可列舉：環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基及環庚基甲基等之C3-C7環烷基取代C1-C4烷基。In the description of this case, "cycloalkyl-alkyl" can be exemplified by C3-C7 cycloalkyl substitutions such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl C1-C4 alkyl.

於本案說明書中「芳烷基」可列舉：苯甲基、苯乙基、萘甲基、茀基甲基等之C7-C13芳烷基。In the specification of this case, the "aralkyl group" includes C7-C13 aralkyl groups such as benzyl, phenethyl, naphthylmethyl, and stilbylmethyl.

於本案說明書中「烯基」係直鏈狀、支鏈狀或環狀任一者皆可，且係指具有至少1個(例如1個或2個)雙鍵的不飽和烴基，且可舉例如：乙烯基、烯丙基、1-丙烯基、2-甲基-2-丙烯基、異丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、異丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、5-己烯基、1-環戊烯基、1-環己烯基、3-甲基-3-丁烯基等之C2-C6烯基。In the specification of the present case, the "alkenyl group" can be any one of linear, branched or cyclic, and refers to an unsaturated hydrocarbon group having at least one (for example, one or two) double bonds, and can be exemplified Such as: vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 2 -Pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentene C2-C6 alkenyl groups such as 1-cyclohexenyl and 3-methyl-3-butenyl.

於本案說明書中「炔基」係指直鏈狀、支鏈狀或環狀任一者皆可，且具有至少1個(例如1個或2個)三鍵的不飽和烴基，且可舉例如：乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基等之C2-C6炔基。In the specification of the present case, "alkynyl" refers to an unsaturated hydrocarbon group that can be linear, branched, or cyclic, and has at least one (for example, one or two) triple bonds, and can include, for example ：C2-C6 alkynes such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, etc. base.

於本案說明書中「烷氧基」可為直鏈狀或支鏈狀任一者，且可舉例如：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊基氧基、異戊基氧基、己基氧基等之C1-C6烷氧基。In the specification of this case, the "alkoxy group" can be either linear or branched, and examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, C1-C6 alkoxy such as isobutoxy, second butoxy, tertiary butoxy, pentyloxy, isopentyloxy, and hexyloxy.

於本案說明書中「鹵代烷氧基」係具有1~13個鹵素原子之碳數1至6的直鏈狀或支鏈狀烷氧基(鹵代C1-C6烷氧基)，可舉例如：氟甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、氟乙氧基、1,1,1-三氟乙氧基、單氟-正丙氧基、全氟-正丙氧基、全氟-異丙氧基等之鹵代C1-C6烷氧基，且較佳可列舉鹵代C1-C4烷氧基，更佳為具有1~7個鹵素原子之鹵代C1-C4烷氧基。In the specification of this case, "haloalkoxy" is a linear or branched alkoxy group (halogenated C1-C6 alkoxy) with 1 to 13 halogen atoms and a carbon number of 1 to 6, for example: fluorine Methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro- Halogenated C1-C6 alkoxy groups such as n-propoxy, perfluoro-isopropoxy, etc., preferably halogenated C1-C4 alkoxy groups, more preferably halogenated with 1-7 halogen atoms C1-C4 alkoxy.

於本案說明書中「環烷氧基」可列舉：環丙氧基、環丁氧基、環戊基氧基、環己基氧基及環庚基氧基等之C3-C7環烷氧基。In the specification of this case, the "cycloalkoxy group" includes C3-C7 cycloalkoxy groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.

於本案說明書中「環烷基-烷氧基」可列舉：環丙基甲氧基、環丁基甲氧基、環戊基甲氧基、環己基甲氧基、環庚基甲氧基等之C3-C7環烷基取代C1-C4烷氧基。In the description of this case, "cycloalkyl-alkoxy" can include C3 such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy, etc. -C7 cycloalkyl replaces C1-C4 alkoxy.

於本案說明書中「烷基硫基」可為直鏈狀或支鏈狀任一者，且可舉例如：甲基硫基、乙基硫基、正丙基硫基、異丙基硫基、正丁基硫基、異丁基硫基、第三丁基硫基、正戊基硫基、異戊基硫基、己基硫基等之C1-C6烷基硫基。In the specification of the present case, the "alkylthio group" can be either linear or branched, and examples include methylthio, ethylthio, n-propylthio, isopropylthio, C1-C6 alkylthio groups such as n-butylthio, isobutylthio, tertiary butylthio, n-pentylthio, isopentylthio, hexylthio and the like.

於本案說明書中「環烷基-烷基硫基」可舉例如：環丙基甲基硫基、環丁基甲基硫基、環戊基甲基硫基、環己基甲基硫基及環庚基甲基硫基等之C3-C7環烷基取代C1-C4烷基硫基。In the specification of the present case, "cycloalkyl-alkylthio" includes, for example, cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio and cycloheptyl The C3-C7 cycloalkyl group such as methylthio group is substituted with C1-C4 alkylthio group.

於本案說明書中「單烷基胺基」可舉例如：經甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、第三丁基胺基、正戊基胺基、異戊基胺基、己基胺基等之直鏈狀或支鏈狀的C1-C6烷基進行單取代的胺基。In the description of this case, the "monoalkylamino group" may include, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, An amino group in which a linear or branched C1-C6 alkyl group such as tertiary butylamino group, n-pentylamino group, isopentylamino group, and hexylamino group is monosubstituted.

於本案說明書中「二烷基胺基」可舉例如：經二甲基胺基、二乙基胺基、二(正丙基)胺基、二異丙基胺基、二(正丁基)胺基、二異丁基胺基、二(第三丁基)胺基、二(正戊基)胺基、二異戊基胺基、二己基胺基、甲基乙基胺基、甲基異丙基胺基等之相同或相異的直鏈狀或支鏈狀的C1-C6烷基進行二取代的胺基。In the description of this case, the "dialkylamino group" can be, for example, dimethylamino group, diethylamino group, di(n-propyl)amino group, diisopropylamino group, di(n-butyl) Amino, diisobutylamino, di(tertiary butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, methyl An amino group in which the same or different linear or branched C1-C6 alkyl groups such as isopropylamino group are disubstituted.

於本案說明書中「環烷基胺基」可舉例如：具有1個或2個前述所列舉的環烷基等之胺基。具體而言，包含：N-環丙基胺基、N,N-二環丙基胺基、N-環丁基胺基、N-環戊基胺基、N-環己基胺基、N-環庚基胺基等。In the specification of the present case, the "cycloalkylamino group" includes, for example, an amino group having one or two cycloalkyl groups listed above. Specifically, it includes: N-cyclopropylamino, N,N-dicyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, N- Cycloheptylamino and so on.

於本案說明書中「環烷基-烷基胺基」可舉例如：環丙基甲基胺基、環丁基甲基胺基、環戊基甲基胺基、環己基甲基胺基及環庚基甲基胺基等之C3-C7環烷基取代C1-C4烷基胺基。In the specification of the present case, the "cycloalkyl-alkylamino group" includes, for example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and cycloheptyl C3-C7 cycloalkyl groups such as methylamino groups are substituted for C1-C4 alkylamino groups.

於本案說明書中「醯基」係指烷基羰基或芳基羰基之意。In the specification of the present case, "acyl" refers to alkylcarbonyl or arylcarbonyl.

於本案說明書中「烷基羰基」可舉例如：甲基羰基、乙基羰基、正丙基羰基、異丙基羰基、正丁基羰基、異丁基羰基、第三丁基羰基、正戊基羰基、異戊基羰基、己基羰基等之直鏈狀或支鏈狀的(C1-C6烷基)羰基。In the description of the present case, the "alkylcarbonyl group" includes, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tertiary butylcarbonyl, n-pentyl Linear or branched (C1-C6 alkyl)carbonyl such as carbonyl, isopentylcarbonyl, and hexylcarbonyl.

於本案說明書中「芳基羰基」可列舉：苯基羰基、萘基羰基、茀基羰基、蒽基羰基、聯苯基羰基、四氫萘基羰基、

Figure 107117996-A0304-12-0020-3
基羰基、2,3-二氫-1,4-二氧雜萘基羰基、二氫茚基羰基及菲基羰基等之(C6-C13芳基)羰基。In the description of this case, the "arylcarbonyl group" includes: phenylcarbonyl, naphthylcarbonyl, stilbylcarbonyl, anthrylcarbonyl, biphenylcarbonyl, tetrahydronaphthylcarbonyl,
Figure 107117996-A0304-12-0020-3
(C6-C13 aryl) carbonyl groups such as carbonyl carbonyl, 2,3-dihydro-1,4-dioxonaphthyl carbonyl, dihydroindenyl carbonyl and phenanthryl carbonyl.

於本案說明書中「醯基胺基」係指烷基羰基胺基或芳基羰基胺基之意。In the specification of the present case, "amino" refers to an alkylcarbonylamino group or an arylcarbonylamino group.

於本案說明書中「烷基羰基胺基」可舉例如：甲基羰基胺基、乙基羰基胺基、正丙基羰基胺基、異丙基羰基胺基、正丁基羰基胺基、異丁基羰基胺基、第三丁基羰基胺基、正戊基羰基胺基、異戊基羰基胺基、己基羰基胺基等之直鏈狀或支鏈狀的(C1-C6烷基)羰基胺基。In the description of the present case, the "alkylcarbonylamino group" includes, for example, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutyl Linear or branched (C1-C6 alkyl) carbonyl amines such as carbonyl amine group, tertiary butyl carbonyl amine group, n-pentyl carbonyl amine group, isopentyl carbonyl amine group, hexyl carbonyl amine group, etc. base.

於本案說明書中「芳基羰基胺基」可舉例如：苯基羰基胺基、萘基羰基胺基、茀基羰基胺基、蒽基羰基胺基、聯苯基羰基胺基、四氫萘基羰基胺基、

Figure 107117996-A0304-12-0020-3
基羰基胺基、2,3-二氫-1,4-二氧雜萘基羰基胺基、二氫茚基羰基胺基、菲基羰基胺基等之(C6-C13芳基)羰基胺基。In the description of this case, the "arylcarbonylamino group" includes, for example, phenylcarbonylamino group, naphthylcarbonylamino group, stilbene carbonylamino group, anthrylcarbonylamino group, biphenylcarbonylamino group, tetrahydronaphthyl Carbonylamino group,
Figure 107117996-A0304-12-0020-3
(C6-C13 aryl)carbonylamino group, 2,3-dihydro-1,4-dioxonaphthylcarbonylamino group, dihydroindenylcarbonylamino group, phenanthrylcarbonylamino group, etc. .

於本案說明書中「醯基氧基」係指烷基羰基氧基或芳基羰基氧基之意。In the specification of the present case, "acyloxy" means alkylcarbonyloxy or arylcarbonyloxy.

於本案說明書中「烷基羰基氧基」可舉例如：甲基羰基氧基、乙基羰基氧基、正丙基羰基氧基、異丙基羰基氧基、正丁基羰基氧基、異丁基羰基氧基、第三丁基羰基氧基、正戊基羰基氧基、異戊基羰基氧基、己基羰基氧基等之直鏈狀或支鏈狀的(C1-C6烷基)羰基氧基。In the description of this case, the "alkylcarbonyloxy group" includes, for example, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutyl Benzylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, hexylcarbonyloxy and other linear or branched (C1-C6 alkyl)carbonyloxy base.

於本案說明書中「芳基羰基氧基」可舉例如：苯基羰基氧基、萘基羰基氧基、茀基羰基氧基、蒽基羰基氧基、聯苯基羰基氧基、四氫萘基羰基氧基、

Figure 107117996-A0304-12-0020-3
基羰基氧基、2,3-二氫-1,4-二氧雜萘基羰基氧基、二氫茚基羰基氧基、菲基羰基氧基等之(C6-C13芳基)羰基氧基。In the specification of this case, "arylcarbonyloxy" includes, for example, phenylcarbonyloxy, naphthylcarbonyloxy, stilbylcarbonyloxy, anthrylcarbonyloxy, biphenylcarbonyloxy, and tetrahydronaphthyloxy. Carbonyloxy,
Figure 107117996-A0304-12-0020-3
Carbonyloxy, 2,3-dihydro-1,4-dioxonaphthylcarbonyloxy, indenylcarbonyloxy, phenanthrylcarbonyloxy, etc. (C6-C13 aryl)carbonyloxy .

於本案說明書中「烷氧基羰基」可為直鏈狀或支鏈狀任一者，且可舉例如：甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧基羰基、丁氧基羰基、異丁氧基羰基、第三丁氧基羰基、戊基氧基羰基、異戊基氧基羰基、己基氧基羰基等之(C1-C6烷氧基)羰基。In the specification of this case, the "alkoxycarbonyl group" can be either linear or branched, and examples include: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butyl (C1-C6 alkoxy)carbonyl such as oxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc.

於本案說明書中「芳烷基氧基羰基」可舉例如：苯甲基氧基羰基、苯乙基氧基羰基、萘基甲基氧基羰基、茀基甲基氧基羰基等之(C7-C13芳烷基)氧基羰基。In the specification of this case, the "aralkyloxycarbonyl group" includes, for example, benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, stilbylmethyloxycarbonyl, etc. (C7- C13 aralkyl)oxycarbonyl.

於本案說明書中「飽和雜環基」係指具有至少1個以上(較佳為1~3個)選自於氮原子、氧原子及硫原子之雜原子的單環或多環的飽和雜環基，具體可列舉：嗎啉基、吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、四氫呋喃基、四氫哌喃基、四氫硫苯基、噻唑啶基、噁唑啶基等。In the specification of this case, "saturated heterocyclic group" refers to a monocyclic or polycyclic saturated heterocyclic ring having at least one or more (preferably 1 to 3) heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms Group, specific examples include: morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
Group, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydrosulfanyl, thiazolidinyl, oxazolidinyl and the like.

於本案說明書中「不飽和雜環基」係指，具有至少1個以上(較佳為1~3個)選自於氮原子、氧原子及硫原子之雜原子的，單環或多環的完全不飽和或部分不飽和雜環基，具體可列舉：咪唑基、噻吩基、呋喃基、吡咯基、噁唑基、異噁唑基、噻唑基、異噻唑基、噻二唑基、吡唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、嗒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、異吲哚基、吲唑基、三唑并吡啶基、苯并咪唑基、苯并噁唑基、苯并異噁唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、1,3-二氫異苯并呋喃基、嘌呤基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹唑啉基、喹噁啉基、呔嗪基、亞甲基二氧基苯基、伸乙二氧基苯基、二氫苯并呋喃基等。In the description of the present case, "unsaturated heterocyclic group" refers to those having at least one or more (preferably 1 to 3) heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, monocyclic or polycyclic Fully unsaturated or partially unsaturated heterocyclic groups, specific examples include: imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazole Group, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indolyl, isoindolyl, indazolyl, three Azolopyridyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, 1,3-dihydroisobenzofuranyl, Purinyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, azinyl, methylenedioxyphenyl, ethylenedioxy Phenyl, dihydrobenzofuranyl, etc.

於本案說明書中，「不飽和烴環基」可舉例如：具有至少1個(例如，1~8個)不飽和鍵結的，單環或由複數環構成的碳數5~14之烴環等，且較佳為芳香族烴基，或單環或二環的5~14員環之不飽和烴基。In the specification of the present case, the "unsaturated hydrocarbon ring group" can be, for example, a hydrocarbon ring having at least one (for example, 1 to 8) unsaturated bond, a single ring or a carbon number of 5 to 14 consisting of multiple rings. Etc., and is preferably an aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 14-membered unsaturated hydrocarbon group.

於本案說明書中「芳香族烴基」可舉例如：苯基、萘基、蒽基、菲基、茀基、四氫萘基等之C6-C14之芳香族烴基。In the specification of this case, the "aromatic hydrocarbon group" includes, for example, C6-C14 aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl, phenanthryl, stilbene, and tetrahydronaphthyl.

於本案說明書中，「單環或二環且為5~14員環之不飽和烴基」可舉例如：環戊二烯基、苯基、萘基、四氫萘基、薁基、并環庚三烯基(heptalenyl)等。In the specification of this case, "monocyclic or bicyclic unsaturated hydrocarbon group with 5 to 14 membered rings" includes, for example, cyclopentadienyl, phenyl, naphthyl, tetrahydronaphthyl, azulenyl, and cycloheptyl Trienyl (heptalenyl) and so on.

於本案說明書中，「單環且為5~10員環的不飽和烴基」可舉例如：環戊二烯基、苯基、環辛四烯基等。In the present specification, the "monocyclic and 5- to 10-membered unsaturated hydrocarbon group" includes, for example, cyclopentadienyl, phenyl, and cyclooctatetraenyl.

於本案說明書中「飽和雜環氧基」係指具有選自於氮原子、氧原子及硫原子之雜原子的飽和雜環氧基，具體而言，可列舉：嗎啉基氧基、1-吡咯啶基氧基、哌啶基氧基、哌嗪基氧基、4-甲基-1-哌嗪基氧基、四氫呋喃基氧基、四氫哌喃基氧基、四氫硫苯基氧基、噻唑啶基氧基、噁唑啶基氧基等，且較佳為具有1~3個選自於氮原子、氧原子及硫原子之雜原子的飽和雜環氧基。In the specification of the present case, the "saturated heterocyclic oxy group" refers to a saturated heterocyclic oxy group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, it includes: morpholinyloxy, 1- Pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropiperanyloxy, tetrahydrothiophenyloxy Group, thiazolidinyloxy, oxazolidinyloxy, etc., and preferably a saturated heterocyclic oxy group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.

於本說明書基團的記載中，「CA-CB」係表示碳數為A~B之基團。舉例而言，「C1-C6烷基」表示碳數1~6的烷基，「C6-C14芳香族烴氧基」則是表示鍵結有碳數6~14之芳香族烴基之氧基。又，「A~B員環」係表示構成環的原子數(環員數)為A~B。舉例而言，「4~10員環之含氮飽和雜環基」係指環員數為4~10的含氮飽和雜環基之意。In the description of the group in this specification, "CA-CB" means a group with carbon number from A to B. For example, "C1-C6 alkyl group" means an alkyl group having 1 to 6 carbon atoms, and "C6-C14 aromatic hydrocarbon oxy group" means an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is bonded. In addition, "A~B member ring" means that the number of atoms (number of ring members) constituting the ring is A~B. For example, "a nitrogen-containing saturated heterocyclic group with 4 to 10 members" means a nitrogen-containing saturated heterocyclic group with 4 to 10 ring members.

通式(I)所表示的化合物中，環A表示亦可經交聯，或是亦可形成螺環的具有氮原子之飽和雜環基。如前述通式(I)所示，環A所具有的氮原子係鍵結在羰基或硫代羰基(carbothionyl)，或者亞甲基上。In the compound represented by the general formula (I), ring A represents a saturated heterocyclic group having a nitrogen atom which may be crosslinked or may form a spiro ring. As shown in the aforementioned general formula (I), the nitrogen atom of ring A is bonded to a carbonyl group, a carbothionyl group, or a methylene group.

環A所表示的「單環、橋聯環或螺環的含氮飽和雜環基」中的「單環的含氮飽和雜環基」可列舉：吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基等之單環的具有氮原子之飽和雜環基，較佳為具有作為雜原子之1~3個氮原子、0~1個硫原子及0~2個氧原子之單環的含氮飽和雜環基，且更佳為具有1~2個作為雜原子之氮原子的單環的含氮飽和雜環基，又更佳為具有1~2個作為雜原子之氮原子單環的4~10員環之含氮飽和雜環基，又更佳為吡咯啶基、哌啶基、哌嗪基、吖
Figure 107117996-A0101-12-0012-002
基，或二吖
Figure 107117996-A0101-12-0012-002
基，又更佳為吡咯啶基、哌啶基、吖
Figure 107117996-A0101-12-0012-002
基，或二吖
Figure 107117996-A0101-12-0012-002
基，又更佳為吡咯啶基，或二吖
Figure 107117996-A0101-12-0012-002
基，且又佳為吡咯啶基。The "monocyclic nitrogen-containing saturated heterocyclic group" in the "monocyclic, bridged ring or spirocyclic nitrogen-containing saturated heterocyclic group" represented by ring A includes: pyrrolidinyl, piperidinyl, and piperazinyl Acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
A monocyclic saturated heterocyclic group with a nitrogen atom such as a group, preferably a monocyclic nitrogen-containing saturated heterocyclic group with 1 to 3 nitrogen atoms, 0 to 1 sulfur atom, and 0 to 2 oxygen atoms as heteroatoms Heterocyclic group, and more preferably a monocyclic nitrogen-containing saturated heterocyclic group having 1 to 2 nitrogen atoms as heteroatoms, and more preferably 4~2 monocyclic nitrogen atoms as heteroatoms 10-membered nitrogen-containing saturated heterocyclic group, more preferably pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, or two acridine
Figure 107117996-A0101-12-0012-002
Group, more preferably pyrrolidinyl, piperidinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, or two acridine
Figure 107117996-A0101-12-0012-002
Group, more preferably pyrrolidinyl, or diaz
Figure 107117996-A0101-12-0012-002
Group, and preferably pyrrolidinyl.

環A所表示的「單環、橋聯環或螺環的含氮飽和雜環基」中的「橋聯環的含氮飽和雜環基」可列舉：In the "monocyclic, bridged ring or spirocyclic nitrogen-containing saturated heterocyclic group" represented by ring A, the "bridged ring nitrogen-containing saturated heterocyclic group" can be enumerated:

[化學式16]

Figure 02_image007
[Chemical formula 16]
Figure 02_image007

等，且較佳為：Etc., and preferably:

[化學式17]

Figure 02_image009
[Chemical formula 17]
Figure 02_image009

，且更佳為：, And more preferably:

[化學式18]

Figure 02_image011
[Chemical formula 18]
Figure 02_image011

，且更佳為：, And more preferably:

[化學式19]

Figure 02_image013
[Chemical formula 19]
Figure 02_image013

，且更佳為：, And more preferably:

[化學式20]

Figure 02_image015
[Chemical formula 20]
Figure 02_image015

，且更佳為：, And more preferably:

[化學式21]

Figure 02_image017
[Chemical formula 21]
Figure 02_image017

。.

環A所表示的「單環、橋聯環或螺環的含氮飽和雜環基」中的「螺環的含氮飽和雜環基」可列舉任2個4員環~7員環之含氮飽和雜環結合而成且具有0~2個氧原子之螺環基，且較佳為任2個4員環~7員環之含氮飽和雜環結合而成且具有2個氮原子及0~1個氧原子之7員環~12員環之螺環基，更佳為二氮雜螺庚基、二氮雜螺辛基、二氮雜螺壬基、二氮雜螺癸基、二氮雜螺十一基、氧雜二氮雜螺庚基、氧雜二氮雜螺辛基、氧雜二氮雜螺壬基、氧雜二氮雜螺癸基，或氧雜二氮雜螺十一基，又更佳為二氮雜螺辛基、二氮雜螺壬基、二氮雜螺癸基，或氧雜二氮雜螺壬基，又更佳為2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[3.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，又更佳為2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基，或9-氧雜-二氮雜螺[3.5]壬基，又更佳為2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基，或2,8-二氮雜螺[3.5]壬基，又更佳為2,8-二氮雜螺[3.5]壬基。The "nitrogen-containing saturated heterocyclic group of a spiro ring" in the "monocyclic, bridged ring or spiro-cyclic nitrogen-containing saturated heterocyclic group" represented by ring A can include any two 4-membered to 7-membered ring A spirocyclic group formed by a combination of nitrogen-saturated heterocycles and having 0 to 2 oxygen atoms, and preferably any two 4-membered to 7-membered nitrogen-containing saturated heterocycles combined and having 2 nitrogen atoms and A 7- to 12-membered spirocyclic group with 0 to 1 oxygen atom, more preferably diazaspiroheptyl, diazaspirooctyl, diazaspironyl, diazaspirodecyl, Diazaspiroundecyl, oxadiazaspiroheptyl, oxadiazaspirooctyl, oxadiazaspironyl, oxadiazaspirodecyl, or oxadiazaspirodecyl Spiroundecyl, more preferably diazaspirooctyl, diazaspironyl, diazaspirodecyl, or oxadiazaspironyl, more preferably 2,7-diaza Heterosspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[3.5]decyl, or 9-oxa-diazepine Heterosspiro[3.5]nonyl, more preferably 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5 ]Nonyl, 2,8-diazaspiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably 2,7-diazaspiro[3.4]octane Yl, 3,7-diazaspiro[3.4]octyl, or 2,8-diazaspiro[3.5]nonyl, more preferably 2,8-diazaspiro[3.5]nonyl.

環A所表示的「單環、橋聯環或螺環的含氮飽和雜環基」較佳為具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，且為單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，又更佳為具有1~2個作為雜原子之氮原子單環的4~10員環之含氮飽和雜環基、The "monocyclic, bridged ring or spirocyclic nitrogen-containing saturated heterocyclic group" represented by ring A preferably has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 oxygen atoms as hetero Atom, and is a monocyclic, bridged or spiro ring of 4 to 14-membered nitrogen-containing saturated heterocyclic group, and more preferably a 4- to 10-membered monocyclic ring with 1 to 2 nitrogen atoms as heteroatoms The nitrogen-containing saturated heterocyclic group,

[化學式22]

Figure 02_image019
[Chemical formula 22]
Figure 02_image019

等之橋聯環含氮飽和雜環基，或任2個4員環~7員環之含氮飽和雜環結合而成且具有0~2個氧原子之螺環基，又更佳為具有1~2個作為雜原子之氮原子單環的4~10員環之含氮飽和雜環基、The bridged ring nitrogen-containing saturated heterocyclic group, or any two 4-membered to 7-membered nitrogen-containing saturated heterocyclic group and the spirocyclic group with 0~2 oxygen atoms, and more preferably have 1 to 2 nitrogen-containing saturated heterocyclic groups with 4 to 10 membered rings as a heterocyclic nitrogen atom monocyclic ring,

[化學式23]

Figure 02_image021
[Chemical formula 23]
Figure 02_image021

等之橋聯環含氮飽和雜環基、任2個4員環~7員環之含氮飽和雜環結合而成且具有2個氮原子及0~1個氧原子之7員環~12員環之螺環基，又更佳為吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、Bridged ring nitrogen-containing saturated heterocyclic group, any two 4-membered to 7-membered nitrogen-containing saturated heterocyclic ring combined with 7-membered ring with 2 nitrogen atoms and 0 to 1 oxygen atom~12 The spirocyclic group of the member ring is more preferably pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式24]

Figure 02_image023
[Chemical formula 24]
Figure 02_image023

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，又更佳為吡咯啶基、哌啶基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably pyrrolidinyl, piperidinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式25]

Figure 02_image025
[Chemical formula 25]
Figure 02_image025

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基，或9-氧雜-二氮雜螺[3.5]壬基，又更佳為吡咯啶基、, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably pyrrolidinyl,

[化學式26]

Figure 02_image027
[Chemical formula 26]
Figure 02_image027

，或2,8-二氮雜螺[3.5]壬基，又更佳為吡咯啶基、, Or 2,8-diazaspiro[3.5]nonyl, more preferably pyrrolidinyl,

[化學式27]

Figure 02_image029
[Chemical formula 27]
Figure 02_image029

。.

通式(I)表示的化合物中，環B表示單環或二環的不飽和烴基，或是亦可經側氧基取代的單環或二環的不飽和雜環基。In the compound represented by the general formula (I), ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group, or a monocyclic or bicyclic unsaturated heterocyclic group which may be substituted with a pendant oxy group.

環B所表示的「單環或二環的不飽和烴基」較佳為單環或二環的5~14員環之不飽和烴基，且更佳為苯基，或萘基，又更佳為苯基。The "monocyclic or bicyclic unsaturated hydrocarbon group" represented by ring B is preferably a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members, more preferably phenyl, or naphthyl, and more preferably Phenyl.

環B所表示的「單環或二環的不飽和雜環基」係具有選自於氮原子、氧原子及硫原子之雜原子的，單環或二環的完全不飽和或部分不飽和雜環基，且較佳為具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，且具有至少1個之氮原子、硫原子及氧原子任一者的5~14員環之單環或二環的完全不飽和雜環基或部分不飽和雜環基，且更佳為咪唑基、噻吩基、呋喃基、吡咯基、噁唑基、異噁唑基、噻唑基、異噻唑基、噻二唑基、吡唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、嗒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、異吲哚基、吲哚啉基、吲唑基、三唑并吡啶基、苯并咪唑基、苯并噁唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、苯并噻吩基、苯并呋喃基、嘌呤基、咪唑并吡啶基、喹啉基、異喹啉基、喹唑啉基、喹噁啉基、呔嗪基、亞甲基二氧基苯基、伸乙二氧基苯基、二氫苯并呋喃基、1,3-二氫異苯并呋喃基、二氫苯并噁唑基(例如，2,3-二氫苯并[d]噁唑基)、二氫苯并氧氮雜芑基(例如，3,4-二氫-2H-苯并[b][1,4]氧氮雜芑基)、苯并二噁

Figure 107117996-A0101-12-0054-2
基(例如，苯并[d][1,3]二噁
Figure 107117996-A0101-12-0054-2
基)、二氫苯并二噁嗪基(例如，2,3-二氫苯并[b][1,4]二噁嗪基等)，或二氫苯并噻唑基(例如，2,3-二氫苯并[d]噻唑基)，且更佳為吡啶基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹噁啉基、喹唑啉基、呔嗪基、二氫苯并噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基、苯并二噁
Figure 107117996-A0101-12-0054-2
基、二氫苯并二噁嗪基，或二氫苯并噻唑基，又更佳為吡啶基、吡唑并吡啶基、吲哚基、吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并三唑基、喹啉基、二氫苯并噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基，或二氫苯并噻唑基，又更佳為吲哚基、吲唑基、苯并異噁唑基，或苯并三唑基，又更佳為苯并三唑基。前述環B所表示的單環或二環的不飽和雜環基亦可經側氧基取代的。經側氧基取代之單環或二環的不飽和雜環基可包含例如：2-側氧基-吲哚啉基The "monocyclic or bicyclic unsaturated heterocyclic group" represented by ring B has heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, monocyclic or bicyclic fully unsaturated or partially unsaturated hetero Cyclic group, and preferably has 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and has at least one nitrogen atom, sulfur atom and any one of oxygen atoms The 5- to 14-membered monocyclic or bicyclic fully unsaturated heterocyclic group or partially unsaturated heterocyclic group, and more preferably imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazole Group, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tiazinyl, pyrazolopyridyl, pyrazolopyrimidine Group, indolyl, isoindolyl, indolinyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzene And triazolyl, benzothienyl, benzofuranyl, purinyl, imidazopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, azinyl, methylene two Oxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazolyl (for example, 2,3-dihydrobenzofuranyl) [d]oxazolyl), dihydrobenzoxazepine (for example, 3,4-dihydro-2H-benzo[b][1,4]oxazepine), benzodioxin
Figure 107117996-A0101-12-0054-2
Base (for example, benzo[d][1,3]dioxin
Figure 107117996-A0101-12-0054-2
Group), dihydrobenzodioxazinyl (for example, 2,3-dihydrobenzo[b][1,4]dioxazinyl, etc.), or dihydrobenzothiazolyl (for example, 2,3 -Dihydrobenzo[d]thiazolyl), and more preferably pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indololinyl, indazolyl, benzimidazolyl, benzene Bisisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, azizinyl, dihydrobenzoxanyl Azolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazepine, benzodioxin
Figure 107117996-A0101-12-0054-2
Group, dihydrobenzodioxazinyl, or dihydrobenzothiazolyl, more preferably pyridyl, pyrazolopyridyl, indolyl, indololinyl, indazolyl, benzimidazolyl, Benzisoxazolyl, benzotriazolyl, quinolinyl, dihydrobenzoxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazepine, or dihydro The benzothiazolyl group is more preferably an indolyl group, an indazolyl group, a benzisoxazolyl group, or a benzotriazole group, and still more preferably a benzotriazole group. The monocyclic or bicyclic unsaturated heterocyclic group represented by the aforementioned ring B may be substituted with pendant oxy groups. The monocyclic or bicyclic unsaturated heterocyclic group substituted by the pendant oxy group may include, for example: 2-pendant oxy-indolinyl group

[化學式28]

Figure 02_image031
[Chemical formula 28]
Figure 02_image031

2-側氧基-2,3-二氫苯并[d]噁唑基2-Pendant oxy-2,3-dihydrobenzo[d]oxazolyl

[化學式29]

Figure 02_image033
[Chemical formula 29]
Figure 02_image033

2-側氧基-2,3-二氫苯并[d]噻唑基2-Pendant oxy-2,3-dihydrobenzo[d]thiazolyl

[化學式30]

Figure 02_image035
[Chemical formula 30]
Figure 02_image035

等。經側氧基取代之單環或二環的不飽和雜環基較佳為2-側氧基-吲哚啉基、2-側氧基-2,3-二氫苯并[d]噁唑基，或2-側氧基-2,3-二氫苯并[d]噻唑基，且更佳為2-側氧基-2,3-二氫苯并[d]噁唑基，或2-側氧基-2,3-二氫苯并[d]噻唑基。Wait. The monocyclic or bicyclic unsaturated heterocyclic group substituted by the pendant oxy group is preferably 2-side oxy-indolinyl, 2-side oxy-2,3-dihydrobenzo[d]oxazole Group, or 2-pendant oxy-2,3-dihydrobenzo[d]thiazolyl, and more preferably 2-pendant oxy-2,3-dihydrobenzo[d]oxazolyl, or 2 -Pendant oxy-2,3-dihydrobenzo[d]thiazolyl.

環B較佳為單環或二環且為5~14員環之不飽和烴基；或是亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，且為單環或二環的5~14員環之不飽和雜環基，且更佳為苯基、萘基、吡啶基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、吲哚啉基、2-側氧基-吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹唑啉基、喹噁啉基、呔嗪基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基、苯并二噁

Figure 107117996-A0101-12-0054-2
基、二氫苯并二噁嗪基，或2-側氧基-2,3-二氫苯并[d]噻唑基，且更佳為苯基、萘基、吡啶基、吡唑并吡啶基、吲哚基、吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并三唑基、喹啉基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基，或2-側氧基-2,3-二氫苯并[d]噻唑基，又更佳為苯基、吲哚基、吲唑基、苯并異噁唑基，或苯并三唑基，又更佳為苯并三唑基。Ring B is preferably a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or it can also be substituted by pendant oxy groups, and has 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 3 oxygen atoms are used as heteroatoms, and have at least one nitrogen atom, sulfur atom and oxygen atom, and are monocyclic or bicyclic unsaturated heterocyclic groups of 5 to 14 members, and more Phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indolinyl, 2-side oxy-indolinyl, indazolyl, benzimidazole Group, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, oxazinyl, 2- Pendant oxy-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazepine, benzodioxin
Figure 107117996-A0101-12-0054-2
Group, dihydrobenzodioxazinyl, or 2-side oxy-2,3-dihydrobenzo[d]thiazolyl, and more preferably phenyl, naphthyl, pyridyl, pyrazolopyridyl , Indolyl, indolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzotriazolyl, quinolinyl, 2-side oxy-2,3-dihydrobenzo [d] oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazepine, or 2-pendyl oxy-2,3-dihydrobenzo[d]thiazolyl, More preferred is phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl, and even more preferred is benzotriazolyl.

在通式(I)所表示的化合物中，R1表示硝基或氰基。較佳為氰基。In the compound represented by the general formula (I), R1 represents a nitro group or a cyano group. Preferably it is cyano.

在通式(I)所表示的化合物中，R2表示鹵素原子。較佳為氟原子。當存在有複數個R2時，該等R2係可相同亦可相異。In the compound represented by the general formula (I), R2 represents a halogen atom. Preferably it is a fluorine atom. When there are a plurality of R2, these R2 systems may be the same or different.

在通式(I)所表示的化合物中，l為0~2之整數，較佳為0~1之整數。In the compound represented by the general formula (I), l is an integer of 0-2, preferably an integer of 0-1.

在通式(I)所表示的化合物中，R3表示亦可具有取代基的胺基、C1-C6烷基、鹵素原子、氰基、側氧基、羥基、胺甲醯基、磺基、C1-C6烷氧基，或胺基(C1-C6烷基)基團。當R3存在有複數個時，該等R3可相同亦可相異。In the compound represented by the general formula (I), R3 represents an amine group, a C1-C6 alkyl group, a halogen atom, a cyano group, a pendant oxy group, a hydroxyl group, a carbamethan group, a sulfo group, and C1 -C6 alkoxy, or amino (C1-C6 alkyl) group. When there are a plurality of R3, the R3 may be the same or different.

R3所表示的「C1-C6烷基」可為直鏈狀或支鏈狀任一者，且可舉例如：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、異戊基、己基等，較佳為C1-C4烷基，且更佳為甲基。The "C1-C6 alkyl group" represented by R3 may be linear or branched, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl , Tert-butyl, n-pentyl, isopentyl, hexyl, etc., preferably C1-C4 alkyl, and more preferably methyl.

R3所表示的「單(C1-C6烷基)胺基」可列舉：甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、第三丁基胺基、正戊基胺基、異戊基胺基、己基胺基等，且較佳為單(C1-C4烷基)胺基，且更佳為甲基胺基、乙基胺基，或異丙基胺基。The "mono(C1-C6 alkyl)amino group" represented by R3 includes: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutyl Amino, tertiary butylamino, n-pentylamino, isopentylamino, hexylamino, etc., and preferably a mono(C1-C4 alkyl)amino group, and more preferably a methylamino group , Ethylamino, or isopropylamino.

R3所表示的「二(C1-C6烷基)胺基」可列舉：二甲基胺基、二乙基胺基、二(正丙基)胺基、二異丙基胺基、二(正丁基)胺基、二異丁基胺基、二(第三丁基)胺基、二(正戊基)胺基、二異戊基胺基、二己基胺基、甲基乙基胺基、甲基異丙基胺基等，且較佳為二甲基胺基、二乙基胺基、二(正丙基)胺基、二異丙基胺基、二(正丁基)胺基、二異丁基胺基、二(第三丁基)胺基、二(正戊基)胺基、二異戊基胺基、二己基胺基、甲基乙基胺基，或甲基異丙基胺基，且更佳為二(C1-C4烷基)胺基，又更佳為二甲基胺基。The "bis(C1-C6 alkyl)amino group" represented by R3 includes: dimethylamino group, diethylamino group, di(n-propyl)amino group, diisopropylamino group, and di(n-propyl)amino group. Butyl)amino, diisobutylamino, di(tertiary butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino , Methyl isopropylamino group, etc., and preferably dimethylamino group, diethylamino group, di(n-propyl)amino group, diisopropylamino group, di(n-butyl)amino group , Diisobutylamino, di(tertiary butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, or methyl isopropyl A propylamino group, more preferably a di(C1-C4 alkyl)amino group, and still more preferably a dimethylamino group.

R3所表示的「(C3-C7環烷基)胺基」可列舉：環丙基胺基、環丁基胺基、環戊基胺基、環己基胺基及環庚基胺基等之(C3-C7環烷基)胺基，且較佳為環丙基胺基、環丁基胺基、環戊基胺基、環己基胺基，或環庚基胺基，且更佳為環丁基胺基。The "(C3-C7 cycloalkyl)amino group" represented by R3 includes cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, etc. ( C3-C7 cycloalkyl) amino, and preferably cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, or cycloheptylamino, and more preferably cyclobutyl Amino group.

R3較佳為亦可具有取代基的胺基、C1-C6烷基、鹵素原子、氰基、側氧基、羥基、胺甲醯基、磺基、C1-C6烷氧基，或胺基(C1-C6烷基)基團，且更佳為亦可具有1~2個作為取代基之C1-C6烷基或C3-C7環烷基的胺基、C1-C6烷基、鹵素原子、氰基、側氧基、羥基、胺甲醯基、磺基、C1-C6烷氧基，或胺基(C1-C6烷基)基團，又更佳為胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，又更佳為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基，又更佳為胺基，或甲基，又更佳為胺基。R3 is preferably an amino group which may also have a substituent, a C1-C6 alkyl group, a halogen atom, a cyano group, a pendant oxy group, a hydroxyl group, a carbamethan group, a sulfo group, a C1-C6 alkoxy group, or an amino group ( C1-C6 alkyl) group, and more preferably may have 1-2 C1-C6 alkyl or C3-C7 cycloalkyl amino groups as substituents, C1-C6 alkyl, halogen atom, cyanide Group, pendant oxy group, hydroxyl group, carbamoyl group, sulfo group, C1-C6 alkoxy group, or amine group (C1-C6 alkyl) group, and more preferably amine group, mono- or di-(C1-C6 Alkyl)amino, (C3-C7 cycloalkyl)amino, or C1-C6 alkyl, more preferably amino, methylamino, ethylamino, isopropylamino, dimethyl An amino group, a cyclobutylamino group, or a methyl group, more preferably an amino group, or a methyl group, and still more preferably an amino group.

在通式(I)所表示的化合物中，m為0~2之整數，較佳為0~1之整數。In the compound represented by the general formula (I), m is an integer of 0-2, preferably an integer of 0-1.

在通式(I)所表示的化合物中，R4表示鹵素原子、羥基、硝基、氰基、胺基、羧基、(C2-C7醯基)胺基、(C2-C7醯基)氧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基、亦可具有取代基的胺甲醯基、亦可具有取代基的C2-C6炔基、亦可具有取代基的(C1-C6烷基)羰基、亦可具有取代基的4~14員環之含氮飽和雜環基，或亦可具有取代基的C6-C14芳香族烴基。當R4存在有複數個時，該等R4可相同亦可相異。In the compound represented by the general formula (I), R4 represents a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl) amino group, a (C2-C7 acyl) oxy group, C1-C8 alkyl which may have substituents, C2-C6 alkenyl which may have substituents, C1-C6 alkoxy which may have substituents, C3-C7 cycloalkyl which may also have substituents, Mono- or di-(C1-C6 alkyl)amino group, carbamoyl group which may have substituents, C2-C6 alkynyl group which may have substituents, (C1-C6 alkyl) carbonyl group which may have substituents , A 4- to 14-membered nitrogen-containing saturated heterocyclic group that may have a substituent, or a C6-C14 aromatic hydrocarbon group that may have a substituent. When there are a plurality of R4, the R4 may be the same or different.

於本發明中，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基，或具有取代基的胺甲醯基時，該取代基可舉例如：鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基、(C1-C6烷氧基)(C1-C6烷基)基團等。當該取代基存在有複數個時，其等可相同亦可相異。In the present invention, when at least one R4 is substituted C1-C8 alkyl, substituted C2-C6 alkenyl, substituted C1-C6 alkoxy, substituted C3-C7 ring In the case of an alkyl group or a substituted aminoformyl group, the substituent may include, for example, a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, Monocyclic and 5- to 10-membered unsaturated hydrocarbon group, may have C1-C6 alkyl as a substituent or mono-cyclic and 5- to 10-membered unsaturated hydrocarbon group of aminomethyl, (C2- C7 acyl) oxy group, C1-C6 alkyl group or C2-C7 acyl amino group as a substituent, C3-C7 cycloalkyl group, (C1-C6 alkane) which may also have a hydroxyl group as a substituent Oxy) (C1-C6 alkyl) group and the like. When there are a plurality of such substituents, they may be the same or different.

R4所表示的「亦可具有取代基的C1-C8烷基」中的「C1-C8烷基」較佳為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、己基、庚基，或辛基，且更佳為C1-C6烷基，又更佳為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基，或己基，又更佳為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基，或第三丁基。The "C1-C8 alkyl group" in the "C1-C8 alkyl group which may have substituents" represented by R4 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , Second butyl, tertiary butyl, pentyl, hexyl, heptyl, or octyl, and more preferably C1-C6 alkyl, and more preferably methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, second butyl, tertiary butyl, pentyl, or hexyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , The second butyl group, or the third butyl group.

R4所表示的「亦可具有取代基的C1-C8烷基」中的「取代基」雖可例示如前述之取代基，但較佳為鹵素原子、胺基、羥基、羧基、胺甲醯基、烷基胺甲醯基、醯基胺基、烷氧基、羥基環烷基，或醯基氧基，且更佳為鹵素原子、胺基、羥基、羧基、胺甲醯基、(C1-C6烷基)胺甲醯基、(C2-C7醯基)胺基、C1-C6烷氧基、C3-C7環烷基、羥基(C3-C7環烷基)基團，或(C2-C7醯基)氧基，又更佳為鹵素原子、胺基、羥基、羧基、胺甲醯基、(C1-C6烷基)胺甲醯基、(C1-C6烷基)羰基胺基、C1-C6烷氧基、C3-C7環烷基、羥基(C3-C7環烷基)基團，或(C1-C6烷基)羰基氧基，又更佳為氟原子、胺基、羥基、羧基、胺甲醯基、甲基胺甲醯基、二甲基胺甲醯基、乙醯基胺基、甲氧基、羥基環丙基，或甲基羰基氧基。Although the "substituent" in the "C1-C8 alkyl group which may have a substituent" represented by R4 can be exemplified as the above-mentioned substituent, it is preferably a halogen atom, an amino group, a hydroxyl group, a carboxyl group, or a carbamate group. , Alkylamine methanoyl group, anoylamino group, alkoxy group, hydroxycycloalkyl group, or anoyloxy group, and more preferably halogen atom, amino group, hydroxyl group, carboxyl group, aminomethanyl group, (C1- C6 alkyl) amine methanoyl, (C2-C7 anoyl) amino, C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy (C3-C7 cycloalkyl) group, or (C2-C7 (C1-C6 alkyl) carbonylamino group, (C1-C6 alkyl) carbonylamino group, (C1-C6 alkyl) carbonylamino group, (C1-C6 alkyl) carbonylamino group, (C1-C6 alkyl) amine methanoyl group, (C1-C6 alkyl) carbonylamino group, (C1-C6 alkyl) carboxyl group, halogen atom, amine group, hydroxyl group, carboxyl group, carbamate group, (C1-C6 alkyl) C6 alkoxy, C3-C7 cycloalkyl, hydroxy (C3-C7 cycloalkyl) group, or (C1-C6 alkyl) carbonyloxy group, and more preferably fluorine atom, amino group, hydroxyl group, carboxyl group, Carboxamide, methylcarboxamide, dimethylcarboxamide, acetylamino, methoxy, hydroxycyclopropyl, or methylcarbonyloxy.

R4所表示的「亦可具有取代基的C1-C8烷基」較佳為無取代的C1-C8烷基，或亦可具有作為取代基之鹵素原子、胺基、羥基、羧基、胺甲醯基、(C1-C6烷基)胺甲醯基、(C1-C6烷基)羰基胺基、C1-C6烷氧基、C3-C7環烷基、羥基(C3-C7環烷基)基團或(C1-C6烷基)羰基氧基之C1-C8烷基，且更佳為甲基、乙基、正丙基、異丙基、第三丁基、二氟甲基、三氟甲基、氟乙基、胺基乙基、羥基甲基、羥基乙基、羥基丙基、羥基二甲基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、羧基甲基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、乙醯基胺基乙基、甲氧基乙基、羥基環丙基甲基、羥基環丙基乙基、羥基環丁基甲基，或甲基羰基氧基乙基，又更佳為甲基、乙基、正丙基、第三丁基、二氟甲基、羥基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、甲氧基乙基、羥基環丙基甲基、羥基環丁基甲基，或甲基羰基氧基乙基，又更佳為甲基、二氟甲基、羥基甲基丙基、羥基甲基丁基、羥基環丁基甲基、甲氧基乙基，或羥基環丁基甲基，又更佳為甲基、二氟甲基、羥基甲基丙基、羥基乙基丁基，或羥基環丁基甲基。The "C1-C8 alkyl group which may also have a substituent" represented by R4 is preferably an unsubstituted C1-C8 alkyl group, or may have a halogen atom, an amino group, a hydroxyl group, a carboxyl group, or a urethane as a substituent. Group, (C1-C6 alkyl) carbamoyl, (C1-C6 alkyl) carbonylamino, C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy (C3-C7 cycloalkyl) group Or (C1-C6 alkyl) C1-C8 alkyl of carbonyloxy, and more preferably methyl, ethyl, n-propyl, isopropyl, tertiary butyl, difluoromethyl, trifluoromethyl , Fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxymethyl , Carboxymethyl, methylcarboxylmethyl, dimethylcarboxylmethyl, acetaminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxy ring Propylethyl, hydroxycyclobutylmethyl, or methylcarbonyloxyethyl, more preferably methyl, ethyl, n-propyl, t-butyl, difluoromethyl, hydroxyethyl, hydroxymethyl Propyl, hydroxymethylbutyl, hydroxyethylbutyl, carbamate methyl, methyl carbamate methyl, dimethyl carbamate methyl, methoxyethyl, hydroxycyclopropyl Methyl, hydroxycyclobutylmethyl, or methylcarbonyloxyethyl, more preferably methyl, difluoromethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxycyclobutylmethyl, methoxy Ethyl, or hydroxycyclobutylmethyl, more preferably methyl, difluoromethyl, hydroxymethylpropyl, hydroxyethylbutyl, or hydroxycyclobutylmethyl.

R4所表示的「亦可具有取代基的C2-C6烯基」較佳為無取代的C2-C6烯基，且更佳為乙烯基、烯丙基、1-丙烯基、2-甲基-2-丙烯基、異丙烯基、1-、2-或3-丁烯基、異丁烯基、2-、3-或4-戊烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、5-己烯基、1-環戊烯基、1-環己烯基，或3-甲基-3-丁烯基，又更佳為異丁烯基。The "C2-C6 alkenyl group which may have a substituent" represented by R4 is preferably an unsubstituted C2-C6 alkenyl group, and more preferably a vinyl group, an allyl group, a 1-propenyl group, and a 2-methyl- 2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, isobutenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl 2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohexenyl, or 3-methyl-3-butenyl, and more preferably isobutenyl.

R4所表示的「亦可具有取代基的C2-C6炔基」中的「C2-C6炔基」可列舉：乙炔基、1-或2-丙炔基、1-、2-或3-丁炔基、1-甲基-2-丙炔基等。「亦可具有取代基的C2-C6炔基」較佳為無取代之C2-C6炔基。Examples of the "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have a substituent" represented by R4 include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butanyl Alkynyl, 1-methyl-2-propynyl, etc. The "C2-C6 alkynyl group which may have a substituent" is preferably an unsubstituted C2-C6 alkynyl group.

R4所表示的「亦可具有取代基的C1-C6烷氧基」中的「C1-C6烷氧基」較佳為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊基氧基，或己基氧基，且更佳為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基。The "C1-C6 alkoxy group" in the "C1-C6 alkoxy group which may have substituents" represented by R4 is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, and a n-propoxy group. Butoxy, isobutoxy, second butoxy, third butoxy, pentyloxy, or hexyloxy, and more preferably methoxy, ethoxy, n-propoxy, isopropoxy Oxy, n-butoxy, isobutoxy, second butoxy, tertiary butoxy.

R4所表示的「亦可具有取代基的C1-C6烷氧基」中的「取代基」雖可例示如前述之取代基，但較佳為羥基，或5~14員環的不飽和烴基，且更佳為羥基，或單環且為5~10員環的不飽和烴基，又更佳為羥基，或苯基。Although the "substituent" in the "C1-C6 alkoxy group which may have a substituent" represented by R4 can be exemplified by the above-mentioned substituents, it is preferably a hydroxyl group or an unsaturated hydrocarbon group of 5 to 14 members. It is more preferably a hydroxyl group, or a monocyclic and 5- to 10-membered unsaturated hydrocarbon group, and more preferably a hydroxyl group or a phenyl group.

R4所表示的「亦可具有取代基的C1-C6烷氧基」較佳為亦可具有作為取代基之羥基或5~14員環之不飽和烴基的C1-C6烷氧基，且更佳為亦可具有作為取代基之羥基或單環且為5~10員環的不飽和烴基的C1-C6烷氧基，又更佳為亦可具有作為取代基之羥基或苯基的C1-C6烷氧基，又更佳為甲氧基、羥基丙氧基，或苯甲基氧基。The "C1-C6 alkoxy group which may also have a substituent" represented by R4 is preferably a C1-C6 alkoxy group which may also have a hydroxyl group as a substituent or an unsaturated hydrocarbon group of 5 to 14 members, and more preferably It is a C1-C6 alkoxy group which may also have a hydroxyl group as a substituent or a monocyclic unsaturated hydrocarbon group of 5-10 members, and more preferably a C1-C6 group which may also have a hydroxyl group or a phenyl group as a substituent Alkoxy is more preferably methoxy, hydroxypropoxy, or benzyloxy.

R4所表示的「亦可具有取代基的C3-C7環烷基」較佳為亦可具有作為取代基之羥基烷基、烷氧基烷基、羥基環烷基，或不飽和烴胺甲醯基之C3-C7環烷基，且更佳為亦可具有作為取代基之羥基(C1-C4烷基)基團、(C1-C4烷氧基)(C1-C4烷基)基團、羥基(C3-C7環烷基)基團，或(C6-C14芳香族烴)胺甲醯基之C3-C7環烷基，又更佳為亦可具有作為取代基之羥基(C1-C4烷基)基團、(C1-C4烷氧基)(C1-C4烷基)基團、羥基(C3-C7環烷基)基團，或苯基胺甲醯基之C3-C7環烷基，又更佳為環丙基、羥基甲基環丙基、甲氧基甲基環丙基、羥基環丙基環丙基，或苯基胺甲醯基環丙基，又更佳為環丙基，或羥基甲基環丙基，又更佳為環丙基。The "C3-C7 cycloalkyl group which may also have a substituent" represented by R4 is preferably a hydroxyalkyl group, an alkoxyalkyl group, a hydroxycycloalkyl group, or an unsaturated hydrocarbon amine methyl group which may also have a substituent group. C3-C7 cycloalkyl group, and more preferably may have as a substituent a hydroxyl group (C1-C4 alkyl) group, (C1-C4 alkoxy) (C1-C4 alkyl) group, hydroxyl group (C3-C7 cycloalkyl) group, or C3-C7 cycloalkyl of (C6-C14 aromatic hydrocarbon) amine methanoyl group, and more preferably, it may also have hydroxyl (C1-C4 alkyl) as a substituent ) Group, (C1-C4 alkoxy) (C1-C4 alkyl) group, hydroxy (C3-C7 cycloalkyl) group, or C3-C7 cycloalkyl of phenylaminomethanyl, and More preferably, it is cyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, or phenylaminomethanylcyclopropyl, still more preferably cyclopropyl, Or hydroxymethylcyclopropyl, more preferably cyclopropyl.

R4所表示的「單或二(C1-C6烷基)胺基」較佳為甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、第三丁基胺基、正戊基胺基、異戊基胺基、己基胺基、二甲基胺基、二乙基胺基、二(正丙基)胺基、二異丙基胺基、二(正丁基)胺基、二異丁基胺基、二(第三丁基)胺基、二(正戊基)胺基、二異戊基胺基、二己基胺基、甲基乙基胺基，或甲基異丙基胺基，且更佳為甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、第三丁基胺基、二甲基胺基、二乙基胺基、二(正丙基)胺基、二異丙基胺基、二(正丁基)胺基、二異丁基胺基、二(第三丁基)胺基、甲基乙基胺基，或甲基異丙基胺基，又更佳為二甲基胺基。The "mono- or di-(C1-C6 alkyl)amino group" represented by R4 is preferably a methylamino group, an ethylamino group, a n-propylamino group, an isopropylamino group, a n-butylamino group, and an isopropylamino group. Butylamino, tertiary butylamino, n-pentylamino, isopentylamino, hexylamino, dimethylamino, diethylamino, two (n-propyl)amino, two Isopropylamino, di(n-butyl)amino, diisobutylamino, di(tertiary)amino, di(n-pentyl)amino, diisopentylamino, dihexyl Amino, methylethylamino, or methylisopropylamino, and more preferably methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino , Isobutylamino, tertiary butylamino, dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(n-butyl)amino , Diisobutylamino, di(tertiary butyl)amino, methylethylamino, or methylisopropylamino, more preferably dimethylamino.

R4所表示的「亦可具有取代基的胺甲醯基」較佳為亦可具有作為取代基之烷基之胺甲醯基，且更佳為亦可具有作為取代基之C1-C6烷基之胺甲醯基，又更佳為胺甲醯基、甲基胺甲醯基、二甲基胺甲醯基。The "aminomethyl group which may also have a substituent" represented by R4 is preferably an aminomethyl group which may also have an alkyl group as a substituent, and more preferably a C1-C6 alkyl group which may also have a substituent The amine methionine is more preferably amine methionine, methyl amine methionine, and dimethyl amine methionine.

R4所表示的「亦可具有取代基的(C1-C6烷基)羰基」中的「烷基羰基」可列舉：甲基羰基、乙基羰基、正丙基羰基、異丙基羰基、正丁基羰基、異丁基羰基、第三丁基羰基、正戊基羰基、異戊基羰基、己基羰基等之直鏈狀或支鏈狀的(C1-C6烷基)羰基。Examples of the "alkylcarbonyl group" in the "(C1-C6 alkyl)carbonyl group that may have substituents" represented by R4 include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, and n-butyl Linear or branched (C1-C6 alkyl) carbonyl groups such as carbonyl carbonyl, isobutyl carbonyl, tertiary butyl carbonyl, n-pentyl carbonyl, isopentyl carbonyl, hexyl carbonyl, etc.

R4所表示的「亦可具有取代基的4~14員環之含氮飽和雜環基」中的「具有氮原子之飽和雜環基」可列舉：嗎啉基、吖呾基(azetidinyl)、吡咯啶基、哌啶基、哌嗪基等。The "saturated heterocyclic group with a nitrogen atom" in the "saturated nitrogen-containing heterocyclic group with a 4- to 14-membered ring which may have substituents" represented by R4 includes: morpholinyl, azetidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, etc.

R4所表示的「亦可具有取代基的C6-C14芳香族烴基」可列舉：苯基、甲苯甲醯基(toluyl)、苯二甲基、萘基、蒽基、菲基、茀基、四氫萘基等之C6-C14之亦可具有作為取代基之甲基之芳香族烴基。The "C6-C14 aromatic hydrocarbon group that may have substituents" represented by R4 includes: phenyl, toluyl, xylylene, naphthyl, anthryl, phenanthryl, stilbene, tetrakis Hydronaphthyl and other C6-C14 aromatic hydrocarbon groups may also have a methyl group as a substituent.

R4較佳為鹵素原子、羥基、硝基、氰基、胺基、羧基、(C2-C7醯基)胺基、(C2-C7醯基)氧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基、亦可具有取代基的胺甲醯基、亦可具有取代基的C2-C6炔基、亦可具有取代基的(C1-C6烷基)羰基、亦可具有取代基的4~14員環之含氮飽和雜環基，或亦可具有取代基的C6-C14芳香族烴基，且更佳為鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，又更佳為鹵素原子、硝基、氰基、羧基；亦可具有作為取代基之鹵素原子、胺基、羥基、羧基、胺甲醯基、(C1-C6烷基)胺甲醯基、(C1-C6烷基)羰基胺基、C1-C6烷氧基、C3-C7環烷基、羥基(C3-C7環烷基)基團或(C1-C6烷基)羰基氧基之C1-C6烷基、C2-C6烯基；亦可具有作為取代基之羥基或單環且為5~10員環的不飽和烴基之C1-C6烷氧基；亦可具有作為取代基之羥基、羥基(C1-C4烷基)基團、(C1-C4烷氧基)(C1-C4烷基)基團、羥基(C3-C7環烷基)基團或(C6-C14芳香族烴)取代胺甲醯基之C3-C7環烷基、單或二(C1-C6烷基)胺基；或是亦可具有作為取代基之C1-C6烷基之胺甲醯基，又更佳為氟原子、氯原子、溴原子、碘原子、硝基、氰基、羧基、甲基、乙基、正丙基、異丙基、第三丁基、二氟甲基、三氟甲基、氟乙基、胺基乙基、羥基甲基、羥基乙基、羥基丙基、羥基二甲基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、羧基甲基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、乙醯基胺基乙基、甲氧基乙基、羥基環丙基甲基、羥基環丙基乙基、羥基環丁基甲基、甲基羰基氧基乙基、異丁烯基、甲氧基、羥基丙氧基、環丙基、羥基甲基環丙基、甲氧基甲基環丙基、羥基環丙基環丙基、苯基胺甲醯基環丙基、苯甲基氧基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基，又更佳為氟原子、氯原子、溴原子、硝基、氰基、羧基、甲基、乙基、正丙基第三丁基、二氟甲基、羥基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、甲氧基乙基、羥基環丙基甲基、羥基環丁基甲基、甲基羰基氧基乙基、甲氧基、環丙基、羥基甲基環丙基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基，又更佳為氟原子、氯原子、溴原子、氰基、甲基、二氟甲基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、甲氧基乙基、羥基環丁基甲基，或環丙基，又更佳為氟原子、氯原子、溴原子、氰基、甲基、二氟甲基、羥基甲基丙基、羥基乙基丁基，或羥基環丁基甲基。R4 is preferably a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl group) amino group, a (C2-C7 acyl group) oxy group, and a C1-C8 alkane which may have a substituent Group, C2-C6 alkenyl which may also have substituents, C1-C6 alkoxy which may also have substituents, C3-C7 cycloalkyl which may also have substituents, mono- or di(C1-C6 alkyl) Amino group, aminomethanyl group which may have substituents, C2-C6 alkynyl group which may have substituents, (C1-C6 alkyl) carbonyl group which may have substituents, 4 to 14 which may have substituents A nitrogen-containing saturated heterocyclic group with a member ring, or a C6-C14 aromatic hydrocarbon group that may also have a substituent, and more preferably a halogen atom, a nitro group, a cyano group, a carboxyl group, and a C1-C8 alkyl group that may also have a substituent , C2-C6 alkenyl which may also have substituents, C1-C6 alkoxy which may also have substituents, C3-C7 cycloalkyl which may also have substituents, mono or di (C1-C6 alkyl) amines Group, or a carbamoyl group which may also have a substituent, and more preferably a halogen atom, a nitro group, a cyano group, or a carboxyl group; it may also have a halogen atom, an amino group, a hydroxyl group, a carboxyl group, and a carbamoyl group as a substituent , (C1-C6 alkyl) carbamoyl, (C1-C6 alkyl) carbonylamino, C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy (C3-C7 cycloalkyl) group or (C1-C6 alkyl) C1-C6 alkyl, C2-C6 alkenyl of carbonyloxy group; C1-C6 alkane which may also have a hydroxyl group as a substituent or a monocyclic unsaturated hydrocarbon group of 5-10 members An oxy group; it may also have a hydroxyl group as a substituent, a hydroxyl group (C1-C4 alkyl) group, a (C1-C4 alkoxy group) (C1-C4 alkyl) group, a hydroxyl group (C3-C7 cycloalkyl) Group or (C6-C14 aromatic hydrocarbon) substituted amine methanoyl C3-C7 cycloalkyl, mono- or di-(C1-C6 alkyl)amino group; or C1-C6 alkane as a substituent The amine methanoyl group is more preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a tertiary butyl group, Difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxymethylbutyl, Hydroxyethyl butyl, carboxymethyl, carbamate methyl, methyl carbamate methyl, dimethyl carbamate methyl, acetamido ethyl, methoxyethyl, Hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutenyl, methoxy, hydroxypropoxy, cyclopropyl, hydroxymethylcyclopropyl, Methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, phenylaminomethanylcyclopropyl, benzyloxy, dimethylamino, aminomethanyl, methylaminomethanyl , Or dimethylaminomethanyl, more preferably fluorine atom, chlorine atom, bromine atom, nitro group, cyano group, carboxyl group, methyl group, ethyl group, n-propyl tert-butyl group, difluoromethyl group, Hydroxyethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxamide methyl, methyl Aminomethyl, dimethylaminomethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, methoxy, cyclopropyl Group, hydroxymethylcyclopropyl, dimethylamino, carboxamide, methylcarboxamide, or dimethylcarboxamide, more preferably fluorine atom, chlorine atom, bromine atom, cyanide Group, methyl, difluoromethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, methoxyethyl, hydroxycyclobutylmethyl, or cyclopropyl, more preferably a fluorine atom , Chlorine atom, bromine atom, cyano, methyl, difluoromethyl, hydroxymethylpropyl, hydroxyethylbutyl, or hydroxycyclobutylmethyl.

在通式(I)所表示的化合物中，n為0~5之整數，較佳為0~3之整數。In the compound represented by the general formula (I), n is an integer of 0-5, preferably an integer of 0-3.

在通式(I)所表示的化合物中，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基。當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子。In the compound represented by the general formula (I), R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 may form a pendant oxy group or a thioketone group together. When R5 and R6 are the same or different and represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom.

R5及R6所表示的「C1-C6烷基」可為直鏈狀或支鏈狀任一者，且可舉例如：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、異戊基、己基等，較佳為C1-C4烷基，且更佳為甲基。The "C1-C6 alkyl group" represented by R5 and R6 may be linear or branched, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tertiary butyl, n-pentyl, isopentyl, hexyl, etc. are preferably C1-C4 alkyl, and more preferably methyl.

R5及R6較佳為相同或相異，為氫原子或C1-C6烷基時，又或者亦可R5與R6一起形成側氧基或硫酮基；當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，且較佳為氫原子，或者亦可R5與R6一起形成側氧基。R5 and R6 are preferably the same or different, and when they are a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together can form a pendant oxy or thioketo group; when R5 and R6 are the same or different, they represent hydrogen In the case of an atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, and is preferably a hydrogen atom, or R5 and R6 may form a pendant oxy group together.

通式(I)所表示的聯苯化合物較佳為在式(I)中，環A為單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，且為單環或二環的5~14員環之不飽和雜環基，R1為硝基或氰基，R2為鹵素原子，R3為胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4為鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基，或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、(C2-C7醯基)氧基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l為0~2之整數，　m為0~2之整數，　n為0~5之整數，　當l為2時，2個R2可相同亦可相異，　當m為2時，2個R3可相同亦可相異，　當n為2~5時，2~5個R4可相同亦可相異，之化合物或其鹽。The biphenyl compound represented by the general formula (I) is preferably in the formula (I), the ring A is a monocyclic, bridged ring or spiro ring of 4 to 14-membered nitrogen-containing saturated heterocyclic group, which has 1 ~3 nitrogen atoms, 0~1 sulfur atoms and 0~2 oxygen atoms are used as heteroatoms. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or it can also be pendent oxygen Group substituted, and has 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 3 oxygen atoms as heteroatoms, and has at least one of nitrogen, sulfur and oxygen atoms, and It is a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, R1 is a nitro group or a cyano group, R2 is a halogen atom, R3 is an amino group, a mono- or di-(C1-C6 alkyl)amino group, (C3-C7 cycloalkyl) amino group, or C1-C6 alkyl group, R4 is halogen atom, nitro group, cyano group, carboxyl group, C1-C8 alkyl group which may have substituents, C2 which may also have substituents -C6 alkenyl, C1-C6 alkoxy which may also have substituents, C3-C7 cycloalkyl which may also have substituents, mono- or di(C1-C6 alkyl)amino groups, or may also have substituents When at least one R4 is C1-C8 alkyl with substituents, C2-C6 alkenyl with substituents, C1-C6 alkoxy with substituents, C3-C7 with substituents In the case of a cycloalkyl group or a substituted aminomethyl group, the substituent represents a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, and a monocyclic ring And it is a 5- to 10-membered ring unsaturated hydrocarbon group, which may also have a C1-C6 alkyl group as a substituent or a monocyclic and 5- to 10-membered ring unsaturated hydrocarbon group amine methanoyl group, (C2-C7醯Group) oxy group, C1-C6 alkyl group or C2-C7 amine group as a substituent, C3-C7 cycloalkyl group which may also have a hydroxyl group as a substituent, or (C1-C6 alkoxy Group) (C1-C6 alkyl) group. When there are plural substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together can form a pendant oxy group or Thioketone group, when R5 and R6 are the same or different, represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l is an integer from 0 to 2, and 　m is from 0 to 2 Integer, "n is an integer from 0 to 5," when l is 2, the two R2s can be the same or different, "when m is 2, the two R3s can be the same or different, "when n is 2 to 5, 2~5 R4 can be the same or different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、More preferably, in formula (I), ring A is pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式31]

Figure 02_image037
[Chemical formula 31]
Figure 02_image037

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，環B表示單環或二環的5~14員環之不飽和烴基；或是亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，且為單環或二環的5~14員環之不飽和雜環基，R1為硝基或氰基，R2為鹵素原子，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基，R4為鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基，或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有作為取代基之羥基的C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有作為取代基之C1-C6烷基或是單環且為5~10員環的不飽和烴基之胺甲醯基、C2-C7醯基、亦可具有作為取代基之C1-C6烷基或C2-C7醯基之胺基、亦可具有作為取代基之羥基的C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l為0~2之整數，　m為0~2之整數，　n為0~5之整數，　當l為2時，2個R2可相同亦可相異，　當m為2時，2個R3可相同亦可相異，　當n為2~5時，2~5個R4可相同亦可相異，之化合物或其鹽。, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or it can be substituted by pendant oxy groups and has 0 to 4 Nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms are used as heteroatoms, and have at least one nitrogen atom, sulfur atom and any one of oxygen atoms, and are monocyclic or bicyclic 5~ A 14-membered unsaturated heterocyclic group, R1 is a nitro group or a cyano group, R2 is a halogen atom, R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, Cyclobutylamino group, or methyl group, R4 is a halogen atom, nitro group, cyano group, carboxyl group, C1-C8 alkyl group which may have substituents, C2-C6 alkenyl group which may also have substituents, or Substituent C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, mono- or di(C1-C6 alkyl)amino group, or optionally substituted aminomethanyl group, when at least One R4 is a substituted C1-C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted group In the case of the aminomethanyl group, the substituent represents a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may also have a hydroxyl group as a substituent, a monocyclic and 5- to 10-membered ring Unsaturated hydrocarbon groups, C1-C6 alkyl groups as substituents, or monocyclic and 5- to 10-membered unsaturated hydrocarbon groups such as aminomethanyl groups, C2-C7 acyl groups, may also have as substituents A C1-C6 alkyl or C2-C7 amine group, a C3-C7 cycloalkyl group which may also have a hydroxyl group as a substituent, or a (C1-C6 alkoxy) (C1-C6 alkyl) group. When there are plural substituents, they may be the same or different. R5 and R6 are the same or different, and represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together can form a pendant oxy group or Thioketone group, when R5 and R6 are the same or different, represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l is an integer from 0 to 2, and 　m is from 0 to 2 Integer, "n is an integer from 0 to 5," when l is 2, the two R2s can be the same or different, "when m is 2, the two R3s can be the same or different, "when n is 2 to 5, 2~5 R4 can be the same or different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、More preferably, in formula (I), ring A is pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式32]

Figure 02_image039
[Chemical formula 32]
Figure 02_image039

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，環B表示單環或二環的5~14員環之不飽和烴基；或是亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，且為單環或二環的5~14員環之不飽和雜環基，R1為硝基或氰基，R2為鹵素原子，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基，R4為鹵素原子、硝基、氰基、羧基；亦可具有作為取代基之鹵素原子、胺基、羥基、羧基、胺甲醯基、(C1-C6烷基)胺甲醯基、(C1-C6烷基)羰基胺基、C1-C6烷氧基、(C1-C6烷基)羰基、C3-C7環烷基、羥基(C3-C7環烷基)基團或(C1-C6烷基)羰基氧基之C1-C8烷基、C2-C6烯基；亦可具有作為取代基之羥基或單環且為5~10員環的不飽和烴基之C1-C6烷氧基；亦可具有作為取代基之羥基、羥基(C1-C4烷基)基團、(C1-C4烷氧基)(C1-C4烷基)基團、羥基(C3-C7環烷基)基團或(C6-C14芳香族烴)取代胺甲醯基之C3-C7環烷基、單或二(C1-C6烷基)胺基；或是亦可具有作為取代基之C1-C6烷基之胺甲醯基，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l為0~2之整數，m為0~2之整數，n為0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異，之化合物或其鹽。, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or it can be substituted by pendant oxy groups and has 0 to 4 Nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms are used as heteroatoms, and have at least one nitrogen atom, sulfur atom and any one of oxygen atoms, and are monocyclic or bicyclic 5~ A 14-membered unsaturated heterocyclic group, R1 is a nitro group or a cyano group, R2 is a halogen atom, R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, Cyclobutylamino group, or methyl group, R4 is halogen atom, nitro group, cyano group, carboxyl group; it can also have halogen atom, amino group, hydroxyl group, carboxyl group, aminomethanyl group, (C1-C6 alkane) as a substituent Group) aminoformyl, (C1-C6 alkyl) carbonylamino, C1-C6 alkoxy, (C1-C6 alkyl) carbonyl, C3-C7 cycloalkyl, hydroxyl (C3-C7 cycloalkyl) C1-C8 alkyl group or C2-C6 alkenyl group of (C1-C6 alkyl) carbonyloxy group; C1 of unsaturated hydrocarbon group with a monocyclic ring and a 5- to 10-membered ring may also have a hydroxyl group as a substituent -C6 alkoxy; it can also have hydroxyl group, hydroxyl (C1-C4 alkyl) group, (C1-C4 alkoxy) (C1-C4 alkyl) group, hydroxyl (C3-C7 ring) as a substituent Alkyl) group or (C6-C14 aromatic hydrocarbon) substituted amine methanoyl C3-C7 cycloalkyl, mono- or di-(C1-C6 alkyl)amino group; or C1 as a substituent -C6 alkyl amine methyl group, R5 and R6 are the same or different, representing a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together can form a pendant oxy or thioketone group, when R5 and R6 are the same Or different, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l is an integer from 0 to 2, m is an integer from 0 to 2, and n is an integer from 0 to 5. , When l is 2, two R2s can be the same or different, when m is 2, two R3s can be the same or different, when n is 2~5, 2~5 R4s can be the same or different Different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、哌啶基、哌嗪基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、More preferably, in formula (I), ring A is pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式33]

Figure 02_image041
[Chemical formula 33]
Figure 02_image041

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，環B為苯基、萘基、吡啶基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、吲哚啉基、2-側氧基-吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹噁啉基、喹唑啉基、呔嗪基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基、苯并二噁

Figure 107117996-A0101-12-0054-2
基、二氫苯并二噁嗪基，或2-側氧基-2,3-二氫苯并[d]噻唑基，R1為硝基或氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基(當R3存在有複數個時，該等R3可相同亦可相異)，R4為氟原子、氯原子、溴原子、碘原子、硝基、氰基、羧基、甲基、乙基、正丙基、異丙基、第三丁基、二氟甲基、三氟甲基、氟乙基、胺基乙基、羥基甲基、羥基乙基、羥基丙基、羥基二甲基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、羧基甲基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、乙醯基胺基乙基、甲氧基乙基、羥基環丙基甲基、羥基環丙基乙基、羥基環丁基甲基、甲基羰基氧基乙基、異丁烯基、甲氧基、羥基丙氧基、環丙基、羥基甲基環丙基、甲氧基甲基環丙基、羥基環丙基環丙基、苯基胺甲醯基環丙基、苯甲基氧基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l為0~2之整數，m為0~2之整數，n表示0~3之整數，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B is phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indolinyl, 2- Pendant oxy-indolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, Quinoxolinyl, quinazolinyl, oxazinyl, 2-side oxy-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzene Oxazepine, benzodioxin
Figure 107117996-A0101-12-0054-2
Group, dihydrobenzodioxazinyl, or 2-side oxy-2,3-dihydrobenzo[d]thiazolyl, R1 is nitro or cyano, R2 is fluorine atom, and R2 is in phenyl The above is in the ortho position relative to R1, and R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, a cyclobutylamino group, or a methyl group (when R3 exists When there are plural, these R3 can be the same or different), R4 is fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, cyano group, carboxyl group, methyl group, ethyl group, n-propyl group, isopropyl group , Tertiary butyl, difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxymethylpropyl, Hydroxymethylbutyl, hydroxyethylbutyl, carboxymethyl, carbamate methyl, methyl carbamate methyl, dimethyl carbamate, acetyl carbamate, Methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutenyl, methoxy, hydroxypropoxy, cyclopropyl, hydroxy Methylcyclopropyl, methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, phenylaminomethylcyclopropyl, benzyloxy, dimethylamino, aminomethyl, Methylaminoformyl or dimethylaminoformyl, R5 and R6 are the same or different, representing a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 together can form a pendant oxy or thioketo group , When R5 and R6 are the same or different and represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l is an integer of 0-2, m is an integer of 0-2, n Represents an integer from 0 to 3. When m is 2, two R3s can be the same or different. When n is 2 to 3, 2 to 3 R4s can be the same or different. Compounds or their salts.

又更佳地，在式(I)中，環A為吡咯啶基、哌啶基、吖

Figure 107117996-A0101-12-0012-002
基、二吖
Figure 107117996-A0101-12-0012-002
基、More preferably, in formula (I), ring A is pyrrolidinyl, piperidinyl, acridine
Figure 107117996-A0101-12-0012-002
Base, two acridine
Figure 107117996-A0101-12-0012-002
base,

[化學式34]

Figure 02_image043
[Chemical formula 34]
Figure 02_image043

、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基，或9-氧雜-二氮雜螺[3.5]壬基，環B為苯基、萘基、吡啶基、吡唑并吡啶基、吲哚基、吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并三唑基、喹啉基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基，或2-側氧基-2,3-二氫苯并[d]噻唑基，R1為氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基(當R3存在有複數個時，該等R3可相同亦可相異)，R4為氟原子、氯原子、溴原子、硝基、氰基、羧基、甲基、乙基、正丙基、第三丁基、二氟甲基、羥基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、甲氧基乙基、羥基環丙基甲基、羥基環丁基甲基、甲基羰基氧基乙基、甲氧基、環丙基、羥基甲基環丙基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l為0~2之整數，m為0~2之整數，n表示0~3之整數，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。, 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B is phenyl, naphthyl, pyridyl, pyrazolopyridyl, indolyl, indolinyl, Indazolyl, benzimidazolyl, benzisoxazolyl, benzotriazolyl, quinolinyl, 2-side oxy-2,3-dihydrobenzo[d]oxazolyl, 1,3 -Dihydroisobenzofuranyl, dihydrobenzoxazepine, or 2-side oxy-2,3-dihydrobenzo[d]thiazolyl, R1 is a cyano group, R2 is a fluorine atom, The R2 is in the ortho position relative to R1 on the phenyl group, and R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, a cyclobutylamino group, or a methyl group. (When there are more than one R3, these R3 may be the same or different), R4 is a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, a n-propyl group, the first Tributyl, difluoromethyl, hydroxyethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxamide methyl, methylcarboxamide methyl, dimethyl Carboxamide methyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, methoxy, cyclopropyl, hydroxymethylcyclopropyl, dimethyl Amino group, carbamate, methyl carbamate, or dimethyl carbamate, R5 and R6 are the same or different, representing a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 Together to form a pendant oxy group or thioketone group, when R5 and R6 are the same or different and represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, and l is an integer of 0-2, m is an integer of 0~2, n represents an integer of 0~3, when m is 2, two R3s can be the same or different, when n is 2~3, 2~3 R4s can be the same or different Iso, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式35]

Figure 02_image045
[Chemical formula 35]
Figure 02_image045

或2,8-二氮雜螺[3.5]壬基，環B為苯基、吲哚基、吲唑基、苯并異噁唑基，或苯并三唑基，R1為氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基，或甲基(當R3存在有複數個時，該等R3可相同亦可相異)、R4為氟原子、氯原子、溴原子、氰基、甲基、二氟甲基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、甲氧基乙基、羥基環丁基甲基，或環丙基，R5及R6為氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~2之整數，n表示0~3之整數，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Or 2,8-diazaspiro[3.5]nonyl, ring B is phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl, R1 is cyano, R2 is A fluorine atom, the R2 is present in the ortho position relative to R1 on the phenyl group, R3 is an amino group, or a methyl group (when there are more than one R3, the R3 may be the same or different), R4 is a fluorine atom, Chlorine atom, bromine atom, cyano group, methyl group, difluoromethyl group, hydroxymethylpropyl group, hydroxymethylbutyl group, hydroxyethylbutyl group, methoxyethyl group, hydroxycyclobutylmethyl group, or cyclopropyl group , R5 and R6 are hydrogen atoms, or R5 and R6 can form side oxy groups together, l is an integer from 0 to 2, m is an integer from 0 to 2, n represents an integer from 0 to 3, when m is 2 , 2 R3 can be the same or different, when n is 2~3, 2~3 R4 can be the same or different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式36]

Figure 02_image047
，[Chemical formula 36]
Figure 02_image047
,

環B為苯基、吲哚基、吲唑基、苯并異噁唑基，或苯并三唑基，R1為氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基(當R3存在有複數個時，該等R3可相同亦可相異)，R4為氟原子、氯原子、溴原子、氰基、甲基、二氟甲基、羥基甲基丙基、羥基乙基丁基，或羥基環丁基甲基，R5及R6為氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~2之整數，n表示0~3之整數，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Ring B is phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl, R1 is a cyano group, R2 is a fluorine atom, and the R2 is on the phenyl group relative to R1 in the ortho Position, R3 is an amino group (when there are plural R3, these R3 may be the same or different), R4 is a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a difluoromethyl group, a hydroxymethyl group Alkylpropyl, hydroxyethylbutyl, or hydroxycyclobutylmethyl, R5 and R6 are hydrogen atoms, or R5 and R6 together can form pendant oxy groups, l is an integer from 0 to 2, and m is from 0 to 2 Integer, n represents an integer from 0 to 3. When m is 2, two R3s can be the same or different. When n is 2 to 3, 2 to 3 R4s can be the same or different. The compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式37]

Figure 02_image049
，[Chemical formula 37]
Figure 02_image049
,

環B為苯環，或苯并三唑基，R1為氰基，R2為氟原子，該R2在苯基上相對於R1存在於鄰位，R3為胺基(當R3存在有複數個時，該等R3可相同亦可相異)，R4為氟原子、溴原子、羥基甲基丙基，或羥基乙基丁基，R5及R6為氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~2之整數，n表示0~3之整數，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Ring B is a benzene ring or a benzotriazole group, R1 is a cyano group, R2 is a fluorine atom, the R2 is present in the ortho position relative to R1 on the phenyl group, and R3 is an amino group (when there are more than one R3, These R3 can be the same or different), R4 is fluorine atom, bromine atom, hydroxymethylpropyl, or hydroxyethylbutyl, R5 and R6 are hydrogen atoms, or R5 and R6 together can form pendant oxygen Base, l is an integer of 0~2, m is an integer of 0~2, n is an integer of 0~3, when m is 2, two R3s can be the same or different, when n is 2~3, 2~3 R4 can be the same or different, the compound or its salt.

在本發明之1態樣中，通式(I)表示的聯苯化合物較佳為在式(I)中，環A為單環、或橋聯環的4~8員環之含氮飽和雜環基，其具有1~3個氮原子來作為雜原子，環B為單環之5~8員環的不飽和烴基，或具有1~4個之氮原子來作為雜原子，且為二環的8~14員環之不飽和雜環基，R1為氰基，R2為鹵素原子，R3為胺基，R4為鹵素原子，或亦可具有羥基作為取代基的C1-C8烷基。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6表示氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~2之整數，n為0~3之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。In one aspect of the present invention, the biphenyl compound represented by the general formula (I) is preferably in the formula (I), where the ring A is a monocyclic ring or a 4- to 8-membered nitrogen-containing saturated heterocyclic ring with bridged rings. Cyclic group, which has 1 to 3 nitrogen atoms as heteroatoms, ring B is a monocyclic unsaturated hydrocarbon group with 5 to 8 membered rings, or has 1 to 4 nitrogen atoms as heteroatoms, and is bicyclic R1 is a cyano group, R2 is a halogen atom, R3 is an amino group, R4 is a halogen atom, or a C1-C8 alkyl group with a hydroxyl group as a substituent. When there are plural substituents, they can be the same or different. R5 and R6 represent a hydrogen atom, or R5 and R6 can form a pendant oxy group together, l is an integer from 0 to 2, and m is 0 An integer of ~2, n is an integer of 0~3, when l is 2, the two R2s can be the same or different, when m is 2, the two R3s can be the same or different, when n is 2~ At 3, 2~3 R4 can be the same or different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式38]

Figure 02_image051
，[Chemical formula 38]
Figure 02_image051
,

環B為苯環，或苯并三唑基，R1為氰基，R2為鹵素原子，R3為胺基，R4為鹵素原子，或亦可具有羥基作為取代基的C1-C8烷基。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6表示氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~2之整數，n為0~3之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Ring B is a benzene ring or a benzotriazole group, R1 is a cyano group, R2 is a halogen atom, R3 is an amino group, R4 is a halogen atom, or a C1-C8 alkyl group which may have a hydroxyl group as a substituent. When there are plural substituents, they can be the same or different. R5 and R6 represent a hydrogen atom, or R5 and R6 can form a pendant oxy group together, l is an integer from 0 to 2, and m is 0 An integer of ~2, n is an integer of 0~3, when l is 2, the two R2s can be the same or different, when m is 2, the two R3s can be the same or different, when n is 2~ At 3, 2~3 R4 can be the same or different, the compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式39]

Figure 02_image053
，[Chemical formula 39]
Figure 02_image053
,

環B為苯環，或苯并三唑基，R1為氰基，R2為氟原子，R3為胺基，R4為氟原子、溴原子、或羥基(C1-C8烷基)基團。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6表示氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~1之整數，n為0~3之整數，當l為2時，2個R2可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Ring B is a benzene ring or a benzotriazole group, R1 is a cyano group, R2 is a fluorine atom, R3 is an amino group, and R4 is a fluorine atom, a bromine atom, or a hydroxy (C1-C8 alkyl) group. When there are plural substituents, they can be the same or different. R5 and R6 represent a hydrogen atom, or R5 and R6 can form a pendant oxy group together, l is an integer from 0 to 2, and m is 0 An integer of ~1, n is an integer of 0~3, when l is 2, two R2s can be the same or different, when n is 2~3, 2~3 R4s can be the same or different. Compound or its salt.

又更佳地，在式(I)中，環A為吡咯啶基、More preferably, in formula (I), ring A is pyrrolidinyl,

[化學式40]

Figure 02_image055
，[Chemical formula 40]
Figure 02_image055
,

環B為苯環，或苯并三唑基，R1為氰基，R2為氟原子，R3為胺基，R4為氟原子、溴原子、羥基甲基丙基，或羥基乙基丁基。當該取代基存在有複數個時，其等可相同亦可相異，R5及R6表示氫原子，又或者亦可R5與R6一起形成側氧基，l為0~2之整數，m為0~1之整數，n為0~3之整數，當l為2時，2個R2可相同亦可相異，當n為2~3時，2~3個R4可相同亦可相異，之化合物或其鹽。Ring B is a benzene ring or a benzotriazole group, R1 is a cyano group, R2 is a fluorine atom, R3 is an amino group, and R4 is a fluorine atom, a bromine atom, a hydroxymethylpropyl group, or a hydroxyethylbutyl group. When there are plural substituents, they can be the same or different. R5 and R6 represent a hydrogen atom, or R5 and R6 can form a pendant oxy group together, l is an integer from 0 to 2, and m is 0 An integer of ~1, n is an integer of 0~3, when l is 2, two R2s can be the same or different, when n is 2~3, 2~3 R4s can be the same or different. Compound or its salt.

本發明中具體的聯苯化合物雖可例示藉後述實施例來製造的實施例化合物1~實施例化合物295，但不限定於其等。Although the specific biphenyl compound in the present invention can exemplify Example Compound 1 to Example Compound 295 produced by the examples described below, it is not limited to them.

適合之聯苯化合物可例示如下者：4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈；4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈；5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈-異構物-B；5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-B；5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X；5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X；5’-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X。Suitable biphenyl compounds can be exemplified as follows: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl -Propyl)phenyl]phenyl]-2-fluoro-benzonitrile; 4-[5-[(3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8 -Carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile; 5'-((1S,2S, 4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2``,3-difluoro-4''-(2-hydroxy-2-methyl Propyl)-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-B; 5'-((1S,2S,4R)-rel-2-amine Group-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo [d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B; 5'-((1S, 2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6 ,7-Difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer -X; 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked Benzene]-4-carbonitrile-isomer-X; 5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl )Methyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-5- Yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X.

接下來，針對與本發明有關的化合物之製造法進行說明。Next, the method for producing the compound related to the present invention will be explained.

通式(I)表示的聯苯化合物可例如藉由下述之製造法或實施例所示方法等來製造。但是，通式(I)表示的聯苯化合物之製造法並不限定於該等反應例。[在步驟1~9中，式中，L1、L2及L3分別獨立表示脫離基或是NH2 或OH，W表示羥基、C1-C6烷氧基，或The biphenyl compound represented by the general formula (I) can be produced, for example, by the following production method or the method shown in the examples. However, the manufacturing method of the biphenyl compound represented by general formula (I) is not limited to these reaction examples. [In steps 1-9, in the formula, L1, L2, and L3 each independently represent a leaving group or NH 2 or OH, and W represents a hydroxyl group, a C1-C6 alkoxy group, or

[化學式41]

Figure 02_image057
[Chemical formula 41]
Figure 02_image057

，Q1表示L1或, Q1 means L1 or

[化學式42]

Figure 02_image059
[Chemical formula 42]
Figure 02_image059

，Q2表示L2或, Q2 means L2 or

[化學式43]

Figure 02_image061
[Chemical formula 43]
Figure 02_image061

，X表示氧原子或硫原子，E1表示氫或亦可具有取代基的C1~C6烷基，當E1為亦可具有取代基的C1~C6烷基時，亦可與BOO一起形成環，環A、環B、R1、R2、R3、R4、R5、R6、l、m及n係與前述同義。又，R5a表示C1-C6烷基。], X represents an oxygen atom or a sulfur atom, E1 represents hydrogen or a C1-C6 alkyl group which may also have substituents. When E1 is a C1-C6 alkyl group which may also have substituents, it can also form a ring together with BOO. A, ring B, R1, R2, R3, R4, R5, R6, 1, m, and n have the same meaning as above. In addition, R5a represents a C1-C6 alkyl group. ]

[化學式44]

Figure 02_image063
[Chemical formula 44]
Figure 02_image063

(步驟1)　鈴木反應本步驟係使用通式(II)所表示的化合物，藉由鈴木反應來製造通式(IV)所表示的化合物的方法。(Step 1) "Suzuki reaction This step is a method of producing the compound represented by the general formula (IV) by the Suzuki reaction using the compound represented by the general formula (II).

本步驟可以通常眾所皆知的方法(例如，Chemical Reviews, Vol.95, p.2457, 1995)為準來進行。關於取代基之保護、保護基之去除及變換以及脫離基L1、L2及L3之變換，可適當地進行。This step can be performed by a commonly known method (for example, Chemical Reviews, Vol. 95, p. 2457, 1995). The protection of substituents, the removal and transformation of protecting groups, and the transformation of the leaving groups L1, L2, and L3 can be carried out appropriately.

L1、L2及L3所表示的脫離基可舉例如：氯原子、溴原子或碘原子等之鹵素原子、三氟甲基磺醯氧基、對甲苯基磺醯氧基等之有機磺醯氧基等。The leaving groups represented by L1, L2 and L3 include, for example, halogen atoms such as chlorine, bromine or iodine, and organic sulfonyloxy groups such as trifluoromethylsulfonyloxy and p-tolylsulfonyloxy. Wait.

芳香族硼酸(aromatic boronic acid)或芳香族硼酸(aromatic boronic acid)酯(III)之使用量，相對於通式(II)所表示的化合物1莫耳，可使用0.5~10莫耳，且較佳為0.8~3莫耳。The usage amount of aromatic boronic acid or aromatic boronic acid ester (III) can be 0.5~10 mol relative to 1 mol of the compound represented by general formula (II). Preferably, it is 0.8 to 3 moles.

過渡金屬催化劑可舉例如：乙酸鈀、肆(三苯基膦)鈀、1,1’-雙(二苯基膦基)二茂鐵-鈀(II)二氯化物、雙(二亞苯甲基丙酮)二鈀(0)、參(亞苯甲基丙酮)二鈀(0)等之鈀催化劑、氯化鎳等之鎳催化劑等。Examples of transition metal catalysts include: palladium acetate, tetraphenylphosphine palladium, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, bis(diphenylene) Base acetone) two palladium (0), ginseng (benzylidene acetone) two palladium (0) and other palladium catalyst, nickel chloride and other nickel catalysts

亦可因應需要添加配位子來使用。配位子可列舉：三苯基膦、三環己基膦、(二苯基膦基)二茂鐵、2-二環己基膦基-2’,4’,6’-三異丙基聯苯、Silica-SMAP等。過渡金屬催化劑之使用量雖依催化劑之種類而異，但相對於通式(II)所表示的化合物1莫耳，通常為0.0001~1莫耳，且較佳為0.01~0.5莫耳、配位子之使用量，相對於通式(II)所表示的化合物1莫耳，通常為0.0001~4莫耳，且較佳為0.01~2莫耳。It can also be used by adding ligands as needed. Examples of ligands include: triphenylphosphine, tricyclohexylphosphine, (diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl , Silica-SMAP, etc. Although the amount of transition metal catalyst used varies with the type of catalyst, it is usually 0.0001 to 1 mol, and preferably 0.01 to 0.5 mol, with respect to 1 mol of the compound represented by the general formula (II). The usage amount of zirconia is usually 0.0001 to 4 mol, and preferably 0.01 to 2 mol, relative to 1 mol of the compound represented by the general formula (II).

鹼可舉例如：三乙基胺等之有機胺類、碳酸鈉、碳酸鉀、碳酸銫、磷酸鈉、磷酸三鉀、氫氧化鈉、氫氧化鉀等之鹼金屬鹽、甲氧化鈉、乙氧化鈉、第三丁氧基化鈉、第三丁氧化鉀等之鹼金屬烷氧化物等。鹼之使用量，相對於通式(II)所表示的化合物1莫耳，通常為0.1~10莫耳，且較佳為1~5莫耳。Examples of bases include: organic amines such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide and other alkali metal salts, sodium methoxide, ethoxylation Alkali metal alkoxides such as sodium, tertiary sodium butoxylate, tertiary potassium butoxide, etc. The usage amount of the base is usually 0.1 to 10 mol, and preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (II).

溶劑只要是不會對反應造成不良影響者即可，且可舉例如：甲苯、乙腈、1,2-二甲氧乙烷、四氫呋喃、1,4-二噁烷、乙醇、N,N-二甲基甲醯胺、水或者其等之混合溶劑等。反應時間為0.1~7日，且較佳為0.5~24小時。反應溫度係0℃~溶劑之沸騰溫度，且較佳為20℃~160℃。The solvent may be one that does not adversely affect the reaction, and examples include toluene, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, ethanol, and N,N-dioxane. Methylformamide, water or mixed solvents of these, etc. The reaction time is 0.1 to 7 days, and preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling temperature of the solvent, and preferably 20°C to 160°C.

如此進行而得到的通式(IV)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (IV) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

又，亦可事先進行使通式(II)所表示的化合物，與後述(步驟2)相同地與通式(V)或(VI)所表示的化合物反應，而將L2變換成In addition, the compound represented by the general formula (II) may be reacted with the compound represented by the general formula (V) or (VI) in the same manner as described later (Step 2) to convert L2 into

[化學式45]

Figure 02_image065
[Chemical formula 45]
Figure 02_image065

的反應。Reaction.

(步驟2)　鈴木反應本步驟係使用通式(IV)所表示的化合物，藉由鈴木反應來製造通式(I’)所表示的化合物的方法。(Step 2) "Suzuki reaction This step is a method of producing a compound represented by the general formula (I') by the Suzuki reaction using the compound represented by the general formula (IV).

本步驟可與(步驟1)之方法相同地進行。當L2(當事先進行將L2變換成This step can be performed in the same way as the method of (Step 1). When L2 (when performed in advance, transform L2 into

[化學式46]

Figure 02_image067
[Chemical formula 46]
Figure 02_image067

之反應時，係L1)為硼酸，或硼酸酯衍生物時，於反應中使用化合物(VI)。During the reaction, when L1) is boric acid or a borate derivative, compound (VI) is used in the reaction.

(VI)之L3係與(步驟1)之L1、L2相同，且(VI)之使用量，相對於通式(IV)所表示的化合物1莫耳，通常為1~10莫耳，且較佳為1~5莫耳。The L3 of (VI) is the same as the L1 and L2 of (Step 1), and the usage amount of (VI) is usually 1~10 mol with respect to 1 mol of the compound represented by the general formula (IV). Preferably, it is 1 to 5 moles.

[化學式47]

Figure 02_image069
[Chemical formula 47]
Figure 02_image069

(步驟3)　硼酸酯化反應本步驟係使用通式(IV)所表示的化合物及二硼烷化合物(VIII)，在過渡金屬催化劑、鹼存在下，藉由亦可因應需要添加配位子的硼酸酯化反應來製造將通式(IX)所表示的L2變換成硼酸酯而成之化合物的方法。(Step 3) "Boration reaction This step uses the compound represented by the general formula (IV) and the diborane compound (VIII). In the presence of a transition metal catalyst and a base, ligands can also be added as needed The method of producing a compound obtained by converting L2 represented by the general formula (IX) into a borate ester by the borate reaction of.

二硼烷化合物(VIII)之使用量，相對於通式(IV)所表示的化合物1莫耳，可使用1~10莫耳，且較佳為1~5莫耳。The usage amount of the diborane compound (VIII) can be 1 to 10 mol, and preferably 1 to 5 mol relative to 1 mol of the compound represented by the general formula (IV).

過渡金屬催化劑可與步驟1的情況相同地使用。The transition metal catalyst can be used in the same manner as in the case of step 1.

鹼除了步驟1的情況之外，還可使用乙酸鉀、乙酸鈉等。In addition to the case of step 1, the base may also be potassium acetate, sodium acetate, and the like.

配位子可與步驟1的情況相同地使用，且較佳為Silica-SMAP。The ligand can be used in the same manner as in Step 1, and is preferably Silica-SMAP.

溶劑可與步驟1的情況相同地使用。The solvent can be used in the same way as in the case of step 1.

反應溫度通常為0~200℃，且較佳為50~160℃。反應時間通常為5分~3日，且較佳為5分~10小時。The reaction temperature is usually 0 to 200°C, and preferably 50 to 160°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

亦可在本步驟3之前，對通式(II)所表示的化合物預先導入It is also possible to introduce the compound represented by the general formula (II) before this step 3

[化學式48]

Figure 02_image071
[Chemical formula 48]
Figure 02_image071

並藉由與該步驟3相同的操作於其上對L1進行硼酸酯化反應。And by the same operation as the step 3, the borate reaction of L1 is carried out on it.

[化學式49]

Figure 02_image073
[Chemical formula 49]
Figure 02_image073

(步驟4)　醯胺化反應本步驟係使用通式(VII)所表示的羧酸化合物及通式(X)所表示的胺化合物及縮合劑，藉由醯胺化反應而製造通式(XI)所表示的化合物的方法。(Step 4) "Amination reaction" This step uses the carboxylic acid compound represented by the general formula (VII), the amine compound represented by the general formula (X), and the condensing agent to produce the general formula (XI) by the amination reaction ) The method of the compound represented.

胺化合物(X)之使用量，相對於通式(VII)所表示的化合物1莫耳，可使用0.5~10莫耳，且較佳為0.8~5莫耳。The usage amount of the amine compound (X) can be 0.5-10 mol, and preferably 0.8-5 mol, relative to 1 mol of the compound represented by the general formula (VII).

縮合劑可舉例如：苯并三唑-1-基氧基-參二甲基胺基鏻鹽、4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基嗎啉鎓氯化物、1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺與1-羥基苯并三唑之組合、O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓　六氟磷酸鹽等。其添加量相對於通式(VII)所表示的化合物1莫耳，為1~100莫耳，且較佳為1~5莫耳。Examples of the condensing agent include: benzotriazol-1-yloxy-ginseng dimethylamino phosphonium salt, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl) )-4-methylmorpholinium chloride, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, O-(7 -Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc. The addition amount thereof is 1 to 100 mol, and preferably 1 to 5 mol relative to 1 mol of the compound represented by the general formula (VII).

又，前述反應可因應需要添加鹼。鹼可舉例如：三乙基胺、二異丙基乙基胺、吡啶等之有機鹼，或碳酸鉀等之無機鹼。其添加量相對於通式(VII)所表示的化合物1莫耳，為1~100莫耳，且較佳為1~10莫耳。In addition, the aforementioned reaction may add a base as needed. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine, or inorganic bases such as potassium carbonate. The addition amount thereof is 1 to 100 mol, and preferably 1 to 10 mol relative to 1 mol of the compound represented by the general formula (VII).

溶劑只要是不會對反應產生阻障者就無特別限定，但可舉例如：甲苯、氯仿、四氫呋喃、N,N-二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯啶-2-酮等或其混合溶劑等。The solvent is not particularly limited as long as it does not hinder the reaction, but examples include toluene, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrole Pidine-2-one, etc. or its mixed solvent, etc.

反應溫度通常為-78~200℃，且較佳為0~50℃。反應時間通常為5分~3日，且較佳為5分~10小時。The reaction temperature is usually -78 to 200°C, and preferably 0 to 50°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

如此進行而得到的通式(XI)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (XI) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

[化學式50]

Figure 02_image075
[Chemical formula 50]
Figure 02_image075

(步驟5)　硫化反應本步驟係藉由利用通式(XI)所表示的化合物與硫化試劑之反應來製造通式(XII)所表示的硫醯胺化合物的方法。(Step 5) "Sulfurization reaction This step is a method of producing the thioamide compound represented by the general formula (XII) by using the reaction between the compound represented by the general formula (XI) and a vulcanizing agent.

硫化試劑可舉例如勞森試劑(Lawesson’s reagent)等。其添加量相對於通式(XI)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。Examples of the sulfurization reagent include Lawesson's reagent. The addition amount thereof is 1 to 10 mol, and preferably 1 to 5 mol relative to 1 mol of the compound represented by the general formula (XI).

溶劑可與步驟1的情況相同地使用。The solvent can be used in the same way as in the case of step 1.

反應溫度通常為0~200℃，且較佳為0~100℃。反應時間通常為5分~3日，且較佳為5分~10小時。The reaction temperature is usually 0 to 200°C, and preferably 0 to 100°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

如此進行而得到的通式(XII)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (XII) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

[化學式51]

Figure 02_image077
[Chemical formula 51]
Figure 02_image077

(步驟6)　往1級醇之還元反應本步驟是藉由使用通式(VII)表示的羧酸化合物與還原劑之反應來製造1級醇化合物(XIII)的方法。還原劑可舉例如硼烷、鋁氫化鋰等。又，亦可舉在系統中形成活性酯後的硼氫化鈉、硼氫化鋰等。活性酯化劑可舉與HATU、HOBt一起使用之WSC・HCl等。還原劑之添加量相對於通式(VII)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。活性酯化劑之添加量相對於通式(VII)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。溶劑可與步驟1的情況相同地使用。反應溫度通常為0~200℃，且較佳為0~100℃。反應時間通常為5分~3日，且較佳為5分~10小時。(Step 6) "Reduction reaction to the first-order alcohol This step is a method of producing the first-order alcohol compound (XIII) by using a reaction between a carboxylic acid compound represented by the general formula (VII) and a reducing agent. Examples of the reducing agent include borane and lithium aluminum hydride. In addition, sodium borohydride, lithium borohydride, etc. after forming active esters in the system can also be cited. Examples of active esterification agents include WSC and HCl used with HATU and HOBt. The addition amount of the reducing agent is 1 to 10 mols, and preferably 1 to 5 mols relative to 1 mol of the compound represented by the general formula (VII). The addition amount of the active esterification agent is 1 to 10 mol, and preferably 1 to 5 mol relative to 1 mol of the compound represented by the general formula (VII). The solvent can be used in the same way as in the case of step 1. The reaction temperature is usually 0 to 200°C, and preferably 0 to 100°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

如此進行而得到的通式(XIII)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (XIII) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

[化學式52]

Figure 02_image079
[Chemical formula 52]
Figure 02_image079

(步驟7)　烷基化反應本步驟是藉由使用通式(XIV)表示的醛化合物與烷基金屬試劑之反應來製造2級醇化合物(XV)之方法。烷基金屬試劑可舉例如烷基鋰、烷基鎂試劑等。烷基金屬試劑之添加量相對於通式(XIV)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。溶劑可與步驟5的情況相同地使用。反應溫度通常為-78~200℃，且較佳為-78~0℃。反應時間通常為5分~3日，且較佳為5分~10小時。(Step 7) "Alkylation reaction" This step is a method of producing a secondary alcohol compound (XV) by using a reaction between an aldehyde compound represented by the general formula (XIV) and an alkyl metal reagent. Examples of the alkyl metal reagent include alkyl lithium and alkyl magnesium reagents. The addition amount of the alkyl metal reagent is 1 to 10 mol, and preferably 1 to 5 mol relative to 1 mol of the compound represented by the general formula (XIV). The solvent can be used in the same manner as in step 5. The reaction temperature is usually -78 to 200°C, and preferably -78 to 0°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

如此進行而得到的通式(XV)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (XV) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

[化學式53]

Figure 02_image081
[Chemical formula 53]
Figure 02_image081

(步驟8)　往醛或酮之氧化反應本步驟是使用通式(XVI)表示的醇化合物與氧化劑，製造通式(XVII)表示的醛或酮化合物的方法。(Step 8) "Oxidation reaction to aldehyde or ketone This step is a method of producing an aldehyde or ketone compound represented by general formula (XVII) using an alcohol compound represented by general formula (XVI) and an oxidizing agent.

氧化劑可舉例如二氧化錳、過釕酸四丙銨、三氧化硫吡啶錯合物、戴斯-馬丁過碘烷(DESS-MARTIN periodinane )，氯鉻酸吡啶鎓等。氧化劑之添加量相對於通式(XVI)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。溶劑可與步驟5的情況相同地使用。反應溫度通常為-78~200℃，且較佳為0~100℃。反應時間通常為5分~3日，且較佳為5分~10小時。如此進行而得到的通式(XVII)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。Examples of the oxidizing agent include manganese dioxide, tetrapropylammonium perruthenate, sulfur trioxide pyridine complex, DESS-MARTIN periodinane (DESS-MARTIN periodinane), pyridinium chlorochromate, and the like. The addition amount of the oxidizing agent is 1 to 10 mol, and preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (XVI). The solvent can be used in the same manner as in step 5. The reaction temperature is usually -78 to 200°C, and preferably 0 to 100°C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours. The compound represented by the general formula (XVII) thus obtained can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

[化學式54]

Figure 02_image083
[Chemical formula 54]
Figure 02_image083

(步驟9)　還元的胺基化反應本步驟是對通式(XVII)表示的醛或酮化合物使用通式(X)表示的胺基化合物及還原劑來製造通式(XVIII)表示的化合物之方法。(Step 9) ``Reduced amination reaction This step is to use the amine compound represented by the general formula (X) and a reducing agent to the aldehyde or ketone compound represented by the general formula (XVII) to produce one of the compounds represented by the general formula (XVIII) method.

還原劑可舉例如三乙醯氧基硼氫化鈉、氰基硼氫化鈉、硼氫化鈉等。還原劑之添加量相對於通式(XVII)所表示的化合物1莫耳，為1~10莫耳，且較佳為1~5莫耳。Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride. The addition amount of the reducing agent is 1 to 10 mol, and preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (XVII).

溶劑只要是不會對反應產生阻障者就無特別限定，但可舉例如：甲苯、氯仿、四氫呋喃、二氯甲烷、甲醇、乙醇等，或其等之混合溶劑等。The solvent is not particularly limited as long as it does not hinder the reaction, but examples thereof include toluene, chloroform, tetrahydrofuran, dichloromethane, methanol, ethanol, etc., or mixed solvents thereof.

如此進行而得到的通式(XVIII)所表示的化合物可藉由眾所皆知的分離純化手段，例如濃縮、減壓濃縮、結晶化、溶劑萃取、再沉澱、層析法等來進行分離純化，或不進行分離純化，來交付至下一步驟。The compound represented by the general formula (XVIII) obtained in this way can be separated and purified by well-known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. , Or without separation and purification, to deliver to the next step.

關於取代基W、X、脫離基L1、L2及L3之變換係可適當地進行。The conversion system of the substituents W, X, and leaving groups L1, L2, and L3 can be appropriately performed.

步驟1~9任一者皆可適當地進行取代基之保護、保護基之去除及變換，例如胺基、亞胺基、羥基、羧基、羰基以及如醯胺基與吲哚般具有活性質子之官能基等，可在各製造法中適切的步驟中，使用經保護的試劑，或是依循通常方法，對該官能基導入保護基之後，去除該保護基。Any one of steps 1 to 9 can appropriately carry out the protection of substituents, the removal and transformation of protective groups, such as amino, imino, hydroxyl, carboxy, carbonyl, and those with active protons such as amide and indole. For the functional group and the like, a protected reagent may be used in an appropriate step in each manufacturing method, or the protective group may be removed after introducing a protective group to the functional group according to a usual method.

「胺基或亞胺基的保護基」只要是有該機能者就無特別限定，但可列舉：例如苯甲基、對甲氧基苯甲基、3,4-二甲氧基苯甲基、鄰硝基苯甲基、對硝基苯甲基、二苯甲基、三苯甲基、異丙苯基等之芳烷基；例如甲醯基、乙醯基、丙醯基、丁醯基、特戊醯基、三氟乙醯基、三氯乙醯基等之低級烷醯基；例如苯甲醯基；例如苯基乙醯基、苯氧基乙醯基等之芳基烷醯基；例如甲氧基羰基、乙氧基羰基、丙基氧基羰基、第三丁氧基羰基等之低級烷氧基羰基；例如對硝基苯甲基氧基羰基、苯乙基氧基羰基等之芳烷基氧基羰基；例如三甲基矽基、第三丁基二甲基矽基等之低級烷基矽基；例如四氫哌喃基；例如三甲基矽基乙氧基甲基；例如甲基磺醯基、乙基磺醯基、第三丁基磺醯基等之低級烷基磺醯基等；例如第三丁基亞磺醯基等之低級烷基亞磺醯基等；例如苯磺醯基、甲苯磺醯基等之芳基磺醯基等、例如鄰苯二甲醯亞胺基等之醯亞胺基，特別是以三氟乙醯基、乙醯基、第三丁氧基羰基、苯甲基氧基羰基、三甲基矽基乙氧基甲基、異丙苯基為佳。"Amino group or imino group protecting group" is not particularly limited as long as it has this function, but examples include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl , O-nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl, cumyl and other aralkyl groups; such as formyl, acetyl, propionyl, butyryl, Lower alkane groups such as p-pentyl, trifluoroacetate, trichloroacetate, etc.; for example, benzyl; such as arylalkanol groups such as phenylacetyl and phenoxyacetyl; For example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, and tertiary butoxycarbonyl; such as p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, etc. Aralkyloxycarbonyl; lower alkylsilyl such as trimethylsilyl, tert-butyldimethylsilyl, etc.; such as tetrahydropiperanyl; such as trimethylsilylethoxymethyl; For example, lower alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, tertiary butylsulfinyl, etc.; for example, lower alkylsulfinyl such as tertiary butylsulfinyl, etc.; For example, arylsulfonyl groups such as benzenesulfonyl and toluenesulfonyl groups, etc., such as phthalimide groups such as phthalimide groups, especially trifluoroacetinyl, acetonitrile, and third Butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxymethyl, and cumyl are preferred.

「羥基的保護基」只要是有該機能者就無特別限定，但可列舉：例如甲基、乙基、丙基、異丙基、第三丁基等之低級烷基；例如三甲基矽基、第三丁基二甲基矽基等之低級烷基矽基；例如甲氧基甲基、2-甲氧基乙氧基甲基等之低級烷氧基甲基；例如四氫哌喃基；例如三甲基矽基乙氧基甲基；例如苯甲基、對甲氧基苯甲基、2,3-二甲氧基苯甲基、鄰硝基苯甲基、對硝基苯甲基、三苯甲基等之芳烷基；例如甲醯基、乙醯基、三氟乙醯基等之醯基等，且特別是以甲基、甲氧基甲基、四氫哌喃基、三甲基矽基乙氧基甲基、第三丁基二甲基矽基、乙醯基為佳。The "protecting group for hydroxyl" is not particularly limited as long as it has this function, but examples include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tertiary butyl; for example, trimethylsilyl Lower alkyl silyl groups such as methoxymethyl, 2-methoxyethoxymethyl, etc.; such as lower alkoxymethyl groups such as methoxymethyl, 2-methoxyethoxymethyl, etc.; such as tetrahydropiperan Group; such as trimethylsilyl ethoxymethyl; such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzene Aralkyl groups such as methyl, trityl, etc.; for example, acyl groups such as formyl, acetyl, trifluoroacetyl, etc., and especially methyl, methoxymethyl, and tetrahydropiperan Group, trimethylsilyl ethoxymethyl, tertiary butyldimethylsilyl, acetyl group are preferred.

「羧基的保護基」只要是有該機能者就無特別限定，但可列舉：例如甲基、乙基、丙基、異丙基、第三丁基等之低級烷基；例如2,2,2-三氯乙基等之鹵基低級烷基；例如烯丙基等之低級烯基；例如三甲基矽基乙氧基甲基；例如苯甲基、對甲氧基苯甲基、對硝基苯甲基、二苯甲基、三苯甲基等之芳烷基等，且特別是以甲基、乙基、第三丁基、烯丙基、苯甲基、對甲氧基苯甲基、三甲基矽基乙氧基甲基為佳。The "protecting group of a carboxyl group" is not particularly limited as long as it has this function, but examples include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tertiary butyl; for example, 2,2, Halo-lower alkyl such as 2-trichloroethyl; for example, lower alkenyl such as allyl; for example, trimethylsilylethoxymethyl; for example, benzyl, p-methoxybenzyl, p Aralkyl groups such as nitrobenzyl, benzhydryl, trityl, etc., and especially methyl, ethyl, tertiary butyl, allyl, benzyl, p-methoxybenzene Methyl and trimethylsilyl ethoxymethyl are preferred.

「羰基的保護基」只要是有該機能者就無特別限定，但可列舉：但可舉例如：乙二醇縮酮、三亞甲基縮酮、二甲基縮酮、乙二醇縮醛、三亞甲基縮醛、二甲基縮醛等之縮酮、縮醛等。The "carbonyl protecting group" is not particularly limited as long as it has this function, but it can be exemplified: but for example, ethylene glycol ketal, trimethylene ketal, dimethyl ketal, glycol acetal, Ketals and acetals such as trimethylene acetal and dimethyl acetal.

「如醯胺基與吲哚般具有活性質子之官能基的保護基」只要是有該機能者就無特別限定，但可列舉：例如甲基、乙基、丙基、異丙基、第三丁基等之低級烷基；例如三甲基矽基、第三丁基二甲基矽基等之低級烷基矽基；例如甲氧基甲基、2-甲氧基乙氧基甲基等之低級烷氧基甲基；例如四氫哌喃基；例如三甲基矽基乙氧基甲基；例如苯甲基、對甲氧基苯甲基、2,3-二甲氧基苯甲基、鄰硝基苯甲基、對硝基苯甲基、三苯甲基等之芳烷基；例如甲醯基、乙醯基、三氟乙醯基等之醯基等，且特別是以甲基、甲氧基甲基、四氫哌喃基、三甲基矽基乙氧基甲基、第三丁基二甲基矽基、乙醯基為佳。The "protecting group of a functional group having active protons like amide group and indole" is not particularly limited as long as it has this function, but examples include methyl, ethyl, propyl, isopropyl, and third Lower alkyl such as butyl; such as trimethylsilyl, tertiary butyldimethylsilyl and lower alkylsilyl; such as methoxymethyl, 2-methoxyethoxymethyl, etc. The lower alkoxymethyl; for example, tetrahydropiperanyl; for example, trimethylsilylethoxymethyl; for example, benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl Group, o-nitrobenzyl, p-nitrobenzyl, trityl and other aralkyl groups; such as formyl, acetyl, trifluoroacetyl, etc., and especially Methyl, methoxymethyl, tetrahydropiperanyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl are preferred.

保護基的去除法雖依該保護基的種類及目的化合物之穩定性等而異，但可依據例如文獻記載的方法(參照Protective Groups in Organic Synthesis，第3版，T. W. Greene著，John Wiley & Sons公司，1999年)或以其為準的方法，例如使用酸或鹼之加溶劑分解，亦即例如使0.01莫耳至大過量之酸，且較佳為三氟乙酸、甲酸、鹽酸等，或等莫耳至大過量之鹼，且較佳為氫氧化鉀、氫氧化鈣等作用的方法；藉由使用氫化金屬錯合物等之化學還原或使用鈀-碳催化劑、雷尼鎳催化劑等之接觸還原等來進行。Although the method of removing the protecting group varies depending on the type of the protecting group and the stability of the target compound, for example, it can be based on the method described in the literature (see Protective Groups in Organic Synthesis, 3rd edition, by TW Greene, John Wiley & Sons Company, 1999) or a method based thereon, such as solubilization using acid or alkali, that is, for example, 0.01 mol to a large excess of acid, and preferably trifluoroacetic acid, formic acid, hydrochloric acid, etc., or Mole to a large excess of base, and preferably potassium hydroxide, calcium hydroxide, etc.; by chemical reduction using metal hydride complexes, etc., or using palladium-carbon catalysts, Raney nickel catalysts, etc. Contact reduction and so on to proceed.

通式(I)表示的聯苯化合物可利用通常之分離手段容易的分離純化。如此的手段可例示如溶劑萃取、再結晶、分餾用逆相高速液體層析法、管柱層析法、分餾薄層層析法等。The biphenyl compound represented by the general formula (I) can be easily separated and purified by ordinary separation means. Such means can be exemplified by solvent extraction, recrystallization, reverse phase high speed liquid chromatography for fractionation, column chromatography, and fractional thin layer chromatography.

通式(I)表示的聯苯化合物，在具有光學異構物、立體異構物、轉動異構物、互變異構物等之異構物時，只要未特別記明，則任何異構物、任何混合物皆包括在該化合物中。例如，當通式(I)表示的聯苯化合物存在有光學異構物時，只要未特別記明，從外消旋體離析出來的光學異構物亦包括在該化合物中。該等異構物可藉由本身已眾所皆知的合成手法、分離手法(濃縮、溶劑萃取、管柱層析法、再結晶等)分別以單一化合物的形式獲得。When the biphenyl compound represented by the general formula (I) has isomers such as optical isomers, stereoisomers, rotational isomers, tautomers, etc., unless otherwise specified, any isomers , Any mixture is included in the compound. For example, when the biphenyl compound represented by the general formula (I) has an optical isomer, the optical isomer isolated from the racemate is also included in the compound unless otherwise specified. These isomers can be obtained as single compounds by well-known synthetic methods and separation methods (concentration, solvent extraction, column chromatography, recrystallization, etc.).

如上述般，只要未特別記明，通式(I)表示的聯苯化合物包含各鏡像異構物及其等之混合物任一者。又，通式(I)表示的聯苯化合物亦可為R體及S體之混合物，R體在90%以上者、在95%以上者、在99%以上者，S體在90%以上者、在95%以上者、在99%以上者等。As mentioned above, unless otherwise specified, the biphenyl compound represented by the general formula (I) includes any one of each enantiomer and a mixture thereof. In addition, the biphenyl compound represented by the general formula (I) can also be a mixture of R-body and S-body, with R-body above 90%, 95% or above, 99% or above, and S-body above 90%. , 95% or more, 99% or more, etc.

光學離析的方法可舉例如：使光學離析劑對通式(I)表示的聯苯化合物作用而形成鹽，利用所得到的鹽的溶解度差等而離析其中一鏡像異構物之非鏡像異構物法；在外消旋體的過飽和溶液中，添加作為結晶種之其中一鏡像異構物之優先結晶法；使用掌性管柱之HPLC等管柱層析法等。非鏡像異構物法中可使用的光學離析劑可從例如以下適當地選擇：酒石酸、蘋果酸、乳酸、杏仁酸、10-樟腦磺酸、其等之衍生物等之酸性離析劑；馬錢子鹼、番木鼈鹼、奎寧等之生物鹼化合物、胺基酸衍生物、辛可尼汀(cinchonidine)、α-甲基苯甲胺等之鹼性離析劑。又，不僅在以各鏡像異構物之混合物的形式得到通式(I)表示的聯苯化合物之後如前述般進行光學離析之方法，亦可藉由僅使用經前述方法等進行光學離析而得之鏡像異構物的其中一者來作為通式(I)表示的聯苯化合物之合成原料，來僅得到通式(I)表示的聯苯化合物中的鏡像異構物之其中一者。又，得到作為前述通式(I)表示的聯苯化合物或其原料化合物之鏡像異構物之其中一者的方法，亦可列舉在產生不對稱碳之反應步驟中，藉由調整催化劑等之反應條件來優先得到鏡像異構物之其中一者般的方法等。The method of optical separation may include, for example, the action of an optical separation agent on the biphenyl compound represented by the general formula (I) to form a salt, and the difference in solubility of the resulting salt is used to separate the diastereomers of one of the enantiomers. Material method; In the supersaturated solution of the racemate, the preferential crystallization method of adding one of the enantiomers as the crystal species; the column chromatography method such as HPLC using a palm column. The optical separation agent that can be used in the diastereomer method can be appropriately selected from, for example, acidic separation agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof; Alkaloid compounds such as protonine, saponine, quinine, amino acid derivatives, cinchonidine, α-methylbenzylamine and other alkaline segregants. In addition, not only the method of optical separation as described above after obtaining the biphenyl compound represented by the general formula (I) as a mixture of each enantiomer, but also the method of optical separation using only the aforementioned method or the like. One of the enantiomers of the biphenyl compound represented by the general formula (I) is used as a synthetic raw material for the biphenyl compound represented by the general formula (I) to obtain only one of the enantiomers of the biphenyl compound represented by the general formula (I). In addition, the method for obtaining one of the enantiomers of the biphenyl compound represented by the aforementioned general formula (I) or its raw material compound can also be exemplified in the reaction step of generating asymmetric carbon by adjusting the catalyst, etc. The reaction conditions are preferred to obtain the enantiomers in general methods, etc.

通式(I)表示的聯苯化合物或其鹽亦可為結晶，且結晶形不論為單一或多形混合物皆包括在該化合物或其鹽中。結晶可適用本身已眾所皆知的結晶化法，藉由結晶化而製造。通式(I)表示的聯苯化合物或其鹽可為溶劑合物(例如，水合物等)，亦可為非溶劑合物，任一者皆包括在通式(I)表示的聯苯化合物或其鹽中。以同位素(例如，3 H、14 C、35 S、125 I等)等標定的化合物亦包括在通式(I)表示的聯苯化合物或其鹽中。The biphenyl compound represented by the general formula (I) or its salt may also be crystalline, and whether the crystal form is a single or a polymorphic mixture, it is included in the compound or its salt. The crystal can be produced by crystallization by applying a well-known crystallization method. The biphenyl compound represented by the general formula (I) or its salt may be a solvate (for example, a hydrate, etc.) or a non-solvate, and any one of them is included in the biphenyl compound represented by the general formula (I) Or in its salt. Compounds calibrated with isotopes (for example, 3 H, 14 C, 35 S, 125 I, etc.) are also included in the biphenyl compound represented by the general formula (I) or its salt.

通式(I)表示的聯苯化合物或其製造中間產物中之鹽意指用於有機化學領域中的慣用者。鹽較佳為藥學上容許的鹽。可舉例如：在具有羧基時於該羧基上的鹼加成鹽，或是在具有胺基或鹼性的雜環烷基時於該胺基或鹼性雜環烷基上的酸加成鹽之鹽類。The biphenyl compound represented by the general formula (I) or the salt in the intermediate product thereof means a conventional one used in the field of organic chemistry. The salt is preferably a pharmaceutically acceptable salt. Examples include: base addition salts on the carboxyl group when it has a carboxyl group, or acid addition salts on the amine group or basic heterocycloalkyl group when it has an amino group or a basic heterocycloalkyl group The salt.

該鹼加成鹽可列舉：例如鈉鹽、鉀鹽等之鹼金屬鹽；例如鈣鹽、鎂鹽等之鹼土類金屬鹽；例如銨鹽；例如三甲基胺鹽、三乙基胺鹽、二環己基胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普羅卡因(Procaine)鹽、N,N'-二苯甲基乙二胺鹽等之有機胺鹽等。The base addition salt may include, for example, alkali metal salts such as sodium salt, potassium salt, etc.; for example, alkaline earth metal salts such as calcium salt and magnesium salt; for example, ammonium salt; for example, trimethylamine salt, triethylamine salt, Organic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, Procaine salt, N,N'-benzylethylenediamine salt, etc.

該酸加成鹽可列舉：例如鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽等之無機酸鹽；例如乙酸鹽、甲酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、三氟乙酸鹽等之有機酸鹽；例如甲烷磺酸鹽、羧基乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等之磺酸鹽等。Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc.; for example, acetate, formate, maleate, and fumarate. Organic acid salts such as diacid, tartrate, citrate, ascorbate, trifluoroacetate, etc.; such as methanesulfonate, carboxyethylsulfonate, benzenesulfonate, p-toluenesulfonate, etc. Salt etc.

通式(I)表示的聯苯化合物或其鹽由於其優異LSD1抑制活性，作為用來預防或治療與LSD1相關的疾病之醫藥，較佳為作為用來治療之醫藥，係十分有用。Due to its excellent LSD1 inhibitory activity, the biphenyl compound represented by the general formula (I) or its salt is very useful as a medicine for preventing or treating diseases related to LSD1, preferably as a medicine for treatment.

透過組合使用通式(I)表示的聯苯化合物或其鹽與其他抗腫瘤劑，抗腫瘤效果會增強。通式(I)表示的聯苯化合物或其鹽與其他抗腫瘤劑之組合，可為1個製劑型態(亦即，摻合劑)，亦可為各別2個以上之製劑型態的併用投予。By using the biphenyl compound represented by general formula (I) or its salt in combination with other antitumor agents, the antitumor effect can be enhanced. The combination of the biphenyl compound represented by the general formula (I) or its salt and other antitumor agents can be in one preparation form (that is, admixture), or a combination of two or more preparation forms. Vote.

本發明中的抗腫瘤效果可例如作成腫瘤體積之減少、腫瘤成長之停滯或生存期間之延長等來評價。The anti-tumor effect of the present invention can be evaluated, for example, as reduction in tumor volume, stagnation of tumor growth, or prolongation of survival period.

在一個實施形態中，提供一種將通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑組合而成的抗腫瘤劑。又，在其他實施形態中，提供一種其他抗腫瘤劑之抗腫瘤效果增強劑，其以通式(I)表示的聯苯化合物或其鹽作為有効成分。In one embodiment, there is provided an antitumor agent obtained by combining a biphenyl compound represented by the general formula (I) or a salt thereof with another antitumor agent. Furthermore, in another embodiment, an antitumor effect enhancer of another antitumor agent is provided, which uses the biphenyl compound represented by the general formula (I) or a salt thereof as an active ingredient.

其他抗腫瘤劑並無特別限制，可舉例如代謝拮抗劑、抗腫瘤性抗生素、分子標的藥、鉑系藥劑、植物生物鹼藥劑。Other antitumor agents are not particularly limited, and examples include metabolic antagonists, antitumor antibiotics, molecular target drugs, platinum-based drugs, and plant alkaloid drugs.

代謝拮抗劑可舉5-氟脲嘧啶(5-FU)、5-氟-2’-去氧尿苷 (FdUrd)、替加氟、替加氟・脲嘧啶劑摻合劑(例：UFT)、替加氟・吉美嘧啶・奧提若希劑摻合劑(例：TS-1)、培美曲塞(Pemetrexed)、三氟胸苷、三氟胸苷・替比拉西(Tipyirasil )鹽酸鹽劑摻合劑(例：LONSURF)、吉西他濱、卡培他濱(Capecitabine)、奈拉濱(Nelarabine)、克羅拉濱、阿糖胞苷、DNA甲基化抑制劑(氮雜胞苷、地西他濱、鳥地西他濱等)等，且宜為阿糖胞苷、或氮雜胞苷、地西他濱、鳥地西他濱等DNA甲基化抑制劑，較佳為阿糖胞苷、氮雜胞苷、地西他濱、或鳥地西他濱。Metabolic antagonists include 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FdUrd), tegafur, tegafur and uracil admixtures (example: UFT), Tegafur, Gemeracil, Ortiroxil Agent Blending Agent (Example: TS-1), Pemetrexed (Pemetrexed), Trifluorothymidine, Trifluorothymidine, Tipyirasil Hydrochloride Agent blending agent (e.g. LONSURF), gemcitabine, capecitabine, nelarabine, clorabine, cytarabine, DNA methylation inhibitors (azacytidine, decitabine) It is preferably cytarabine, or azacytidine, decitabine, guandecitabine and other DNA methylation inhibitors, preferably cytarabine , Azacytidine, decitabine, or guandecitabine.

抗腫瘤性抗生素可舉道諾黴素、阿黴素(Doxorubicin)、氨柔比星(Amrubicin)、艾達黴素、泛艾黴素等蒽環系(anthracyclines)抗腫瘤性抗生素，絲裂黴素C、博來黴素等，且宜為蒽環系抗腫瘤性抗生素，較佳為道諾黴素。Anti-tumor antibiotics can include anthracyclines such as daunorubicin, doxorubicin, amrubicin, idamycin, pantoxin and other anthracyclines, and mitomycin C, bleomycin, etc., and is preferably an anthracycline-based anti-tumor antibiotic, preferably daunorubicin.

分子標的藥可舉例如全反式維甲酸或其衍生物、人類MDM2(mouse double minute 2)(HDM2；human double minute 2)抑制劑、或HDAC抑制劑。The molecular target drugs may include, for example, all-trans retinoic acid or its derivatives, human MDM2 (mouse double minute 2) (HDM2; human double minute 2) inhibitors, or HDAC inhibitors.

全反式維甲酸或其衍生物宜為維A酸(ATRA)、或他米巴羅汀(Tamibarotene)，較佳為維A酸(ATRA)。The all-trans retinoic acid or its derivative is preferably retinoic acid (ATRA) or Tamibarotene (Tamibarotene), preferably retinoic acid (ATRA).

人類MDM2(HDM2)抑制劑宜為RG7388(RO5503781)、AMG-232、DS-3032b、RG7112(RO5045337)、SAR405838、或MK-8242，較佳為RG7388。The human MDM2 (HDM2) inhibitor is preferably RG7388 (RO5503781), AMG-232, DS-3032b, RG7112 (RO5045337), SAR405838, or MK-8242, preferably RG7388.

HDAC抑制劑可舉伏立諾他(Vorinostat)、帕比司他、羅米地辛(Romidepsin)、貝利司他(belinostat)等。HDAC inhibitors can include Vorinostat, Pabirestat, Romidepsin, Belinostat and the like.

分子標的藥宜為全反式維甲酸或其衍生物、人類MDM2(HDM2)抑制劑、或若しくはHDAC抑制藥，較佳為維A酸(ATRA)、或RG7388。The molecular target drug is preferably all-trans retinoic acid or its derivatives, human MDM2 (HDM2) inhibitors, or HDAC inhibitors, preferably retinoic acid (ATRA) or RG7388.

鉑系藥劑可舉奧沙利鉑、卡鉑、順鉑、奈達鉑(Nedaplatin)等，且宜為卡鉑、或順鉑。The platinum-based agent may include oxaliplatin, carboplatin, cisplatin, Nedaplatin, etc., and preferably carboplatin or cisplatin.

植物生物鹼藥劑可舉紫杉醇、歐洲紫杉醇(Docetaxel)、長春鹼(Vinblastine)、長春新鹼(Vincristine)、長春地辛(vindesine)、長春瑞濱(Vinorelbine)、艾日布林(Eribulin)等微管抑制藥、愛萊諾迪肯(SN-38)、諾吉替康(Nogitecan)、依託泊苷等拓撲異構酶抑制藥，且宜為紫杉醇、歐洲紫杉醇(Docetaxel)等紫杉烷系微管抑制藥，或愛萊諾迪肯(SN-38)、諾吉替康、依託泊苷等拓撲異構酶抑制藥，較佳為紫杉醇、愛萊諾迪肯(SN-38)、或依託泊苷。Plant alkaloids can include paclitaxel, European paclitaxel (Docetaxel), vinblastine (Vinblastine), vincristine (Vincristine), vindesine (vindesine), vinorelbine (Vinorelbine), Eribulin (Eribulin), etc. Tube inhibitors, topoisomerase inhibitors such as Eleanor Dicken (SN-38), Nogitecan (Nogitecan), Etoposide, etc., and preferably taxane-based drugs such as paclitaxel and European paclitaxel (Docetaxel) Tube inhibitors, or topoisomerase inhibitors such as Eleanor Dicken (SN-38), Nojitecan, Etoposide, etc., preferably Paclitaxel, Eleanor Dicken (SN-38), or Relyon Poside.

其他抗腫瘤劑宜為代謝拮抗劑、抗腫瘤性抗生素、分子標的藥、鉑系藥劑、或植物生物鹼藥劑，較佳為代謝拮抗劑、抗腫瘤性抗生素、全反式維甲酸或其衍生物、人類MDM2(HDM2)抑制劑、HDAC抑制劑、鉑系藥劑、或植物生物鹼藥劑，較佳為代謝拮抗劑、抗腫瘤性抗生素、全反式維甲酸或其衍生物、人類MDM2(HDM2)抑制劑、鉑系藥劑、或植物生物鹼藥劑，較佳為代謝拮抗劑、抗腫瘤性抗生素、全反式維甲酸或其衍生物、人類MDM2(HDM2)抑制劑、鉑系藥劑、拓撲異構酶抑制藥、或紫杉烷系微管抑制藥，較佳為阿糖胞苷、DNA甲基化抑制劑、蒽環系抗腫瘤性抗生素、全反式維甲酸或其衍生物、鉑系藥劑、拓撲異構酶抑制藥、或紫杉烷系微管抑制藥，較佳為阿糖胞苷、氮雜胞苷、地西他濱、鳥地西他濱、道諾黴素、維A酸(ATRA)、RG7388、卡鉑、順鉑、紫杉醇、愛萊諾迪肯(SN-38)、或依託泊苷。Other anti-tumor agents are preferably metabolic antagonists, anti-tumor antibiotics, molecular target drugs, platinum-based drugs, or plant alkaloid drugs, preferably metabolic antagonists, anti-tumor antibiotics, all-trans retinoic acid or derivatives thereof , Human MDM2 (HDM2) inhibitors, HDAC inhibitors, platinum-based medicaments, or plant alkaloid medicaments, preferably metabolic antagonists, anti-tumor antibiotics, all-trans retinoic acid or its derivatives, human MDM2 (HDM2) Inhibitors, platinum-based drugs, or plant alkaloid drugs, preferably metabolic antagonists, anti-tumor antibiotics, all-trans retinoic acid or derivatives thereof, human MDM2 (HDM2) inhibitors, platinum-based drugs, topoisomerism Enzyme inhibitors or taxane-based microtubule inhibitors, preferably cytarabine, DNA methylation inhibitors, anthracycline-based antitumor antibiotics, all-trans retinoic acid or its derivatives, platinum-based drugs , Topoisomerase inhibitors, or taxane-based microtubule inhibitors, preferably cytarabine, azacytidine, decitabine, guandecitabine, daunorubicin, tretinoin (ATRA), RG7388, carboplatin, cisplatin, paclitaxel, Ailenodicken (SN-38), or etoposide.

本發明中作為對象之腫瘤，只要在能達到抗腫瘤效果之增強效果的範圍，並無特別限制，宜為通式(I)表示的聯苯化合物或其鹽會發揮抗腫瘤效果之腫瘤，較佳為與LSD1有關的惡性腫瘤。The target tumor of the present invention is not particularly limited as long as it can achieve the enhancement effect of the anti-tumor effect. It is preferably a tumor in which the biphenyl compound represented by the general formula (I) or its salt exerts an anti-tumor effect. It is preferably a malignant tumor related to LSD1.

在此，「與LSD1有關的惡性腫瘤」可舉因缺失、抑止及/或抑制LSD1之機能，而降低發病率，減輕、和緩症狀，及/或痊癒之惡性腫瘤。成為對象的惡性腫瘤雖無特別限制，但可舉例如：頭頸部癌、食道癌、胃癌、結腸癌、直腸癌、肝癌、膽囊/膽管癌、膽道癌、胰臟癌、肺癌、乳癌、卵巢癌、子宮頸癌、子宮體癌、腎癌、膀胱癌、前列腺癌、睪丸腫瘤、骨/軟組織腫瘤、白血病、骨髓增生異常症候群、慢性骨髄增殖性疾病、惡性淋巴瘤、多發性骨髓瘤、皮膚癌、腦腫瘤、中皮瘤等。較佳可舉肺癌(非小細胞肺癌、小細胞肺癌等)、白血病、骨髄增生異常症候群。Here, "malignant tumors related to LSD1" can refer to malignant tumors that are missing, inhibited, and/or inhibited the function of LSD1, thereby reducing the incidence, alleviating, alleviating symptoms, and/or healing. The target malignant tumor is not particularly limited, but for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder/bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer Cancer, cervical cancer, uterine body cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumors, bone/soft tissue tumors, leukemia, myelodysplastic syndrome, chronic bone malignant proliferative disease, malignant lymphoma, multiple myeloma, skin Cancer, brain tumor, mesothelioma, etc. Preferable examples include lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), leukemia, and bone malignant hyperplasia syndrome.

在將聯苯化合物或其鹽及其他抗腫瘤劑使用來作為醫藥時，可因應需要來摻合藥學載劑，並可因應預防或治療目的來採用1個或複數個投予形態。該形態為可例如口服劑、注射劑、栓劑、軟膏劑、貼片劑等任一者即可。在聯苯化合物或其鹽之情況，宜為口服劑。該等投予形態分別可藉由習於此藝者所眾所皆知慣用的製劑方法來製造。When biphenyl compounds or their salts and other anti-tumor agents are used as medicines, pharmaceutical carriers can be blended as needed, and one or more administration forms can be adopted for prevention or treatment purposes. This form may be any of, for example, oral preparations, injections, suppositories, ointments, patches, and the like. In the case of a biphenyl compound or its salt, it is preferably an oral agent. These dosage forms can be manufactured by the well-known and customary preparation methods for those who are accustomed to the art.

通式(I)表示的聯苯化合物或其鹽、及其他抗腫瘤劑之投予時程可在達成抗腫瘤效果之增強效果的範圍適宜選擇，且各有效成分可同時或隔著間隔個別投予。個別投予時，何者先投皆無妨。The administration schedule of the biphenyl compound represented by the general formula (I) or its salt, and other antitumor agents can be appropriately selected within the scope of achieving the enhancement effect of the antitumor effect, and each active ingredient can be administered simultaneously or individually at intervals Give. In the case of individual voting, it doesn't matter which one vote first.

通式(I)表示的聯苯化合物或其鹽、及其他抗腫瘤劑，基於各有效成分之投予形態或投予時程，可將各有效成分分成複數個劑形來製劑化，亦可整合成一個劑形來製劑化(亦即，作為摻合劑來製劑化)。又，可將各製劑整合到適合併用的1個封包來製造販賣，又，亦可將各製劑分開到個別封包來製造販賣。The biphenyl compound represented by the general formula (I) or its salt, and other antitumor agents can be formulated by dividing each active ingredient into a plurality of dosage forms based on the dosage form or time course of each active ingredient, or Integrate into a dosage form to be formulated (that is, to be formulated as a blending agent). In addition, each formulation can be manufactured and sold by integrating each formulation into a single package suitable for combined use, or each formulation can be divided into individual packages for manufacturing and selling.

藥學載劑可使用作為製劑素材所慣用的各種有機或是無機載劑物質，而作為固形製劑中的賦形劑、結合劑、崩解劑、潤滑劑、塗布劑；液狀製劑中的溶劑、助溶劑、懸浮化劑、等張化劑、pH調整劑/緩衝劑、無痛劑等來摻合。又，亦可因應需要來使用防腐劑、抗氧化劑、著色劑、口味調節/氣味改善劑、穩定劑等之製劑添加物。Pharmaceutical carriers can use various organic or inorganic carrier substances commonly used as preparation materials, and as excipients, binders, disintegrating agents, lubricants, and coating agents in solid preparations; solvents in liquid preparations, Co-solvents, suspending agents, isotonic agents, pH adjusters/buffering agents, soothing agents, etc. are blended. In addition, preservatives, antioxidants, colorants, taste modifiers/odor improvers, stabilizers, and other formulation additives can also be used as needed.

在調製口服用固形製劑時，可使用賦形劑、結合劑、崩解劑、潤滑劑、著色劑、口味調節/氣味改善劑等，並依據通常方法製造錠劑、塗覆錠劑、顆粒劑、散劑、膠囊劑等。When preparing solid preparations for oral administration, excipients, binders, disintegrating agents, lubricants, colorants, taste regulators/odor improving agents, etc. can be used, and tablets, coated tablets, and granules can be manufactured according to the usual methods. , Powders, capsules, etc.

賦形劑可列舉：乳糖、白糖、D-甘露糖醇、葡萄糖、澱粉、碳酸鈣、高嶺土、微結晶纖維素、無水矽酸等。結合劑可列舉：水、乙醇、1-丙醇、2-丙醇、單糖漿、葡萄糖液、α-澱粉液、明膠液、D-甘露糖醇、羧基甲基纖維素、羥基丙基纖維素、羥基丙基澱粉、甲基纖維素、乙基纖維素、蟲膠、磷酸鈣、聚乙烯吡咯啶酮等。崩解劑可列舉：乾燥澱粉、褐藻酸鈉、洋菜粉末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸單甘油酯、乳糖等。潤滑劑可列舉：純化滑石、硬脂酸鹽鈉、硬脂酸鎂、硼砂、聚乙二醇等。著色劑可列舉：氧化鈦、氧化鐵等。口味調節/氣味改善劑可列舉：白糖、橙皮、檸檬酸、酒石酸等。Excipients include lactose, white sugar, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, anhydrous silicic acid and the like. Binders include: water, ethanol, 1-propanol, 2-propanol, monosyrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose , Hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, polyethylene glycol, and the like. Examples of colorants include titanium oxide and iron oxide. Examples of taste adjusting/odor improving agents include sugar, orange peel, citric acid, tartaric acid, and the like.

在調製口服用液體製劑時，可使用口味調節劑、緩衝劑、穩定劑、氣味改善劑等，並藉由通常方法來製造内服液劑、劑糖漿劑、劑酏劑等。When preparing liquid preparations for oral administration, taste modifiers, buffers, stabilizers, odor improving agents, etc. can be used, and oral liquids, syrups, elixirs, etc. can be produced by ordinary methods.

口味調節/氣味改善劑可為前述所列舉者；緩衝劑可列舉檸檬酸鈉等；穩定劑則可列舉黃蓍樹膠、阿拉伯膠、明膠等。依需要，亦可施以腸溶性塗層，或這在以效果持續為目的時，藉由所眾所皆知的方法對口服製劑施以塗布。如此的塗布劑可列舉：羥基丙基甲基纖維素、乙基纖維素、羥基甲基纖維素、羥基丙基纖維素、聚氧基乙二醇、Tween 80(註冊商標)等。The taste adjusting/odor improving agent may be those listed above; the buffering agent may be sodium citrate, etc.; the stabilizer may be tragacanth gum, acacia gum, gelatin, etc. If necessary, an enteric coating may be applied, or when the effect is to last, the oral preparation may be applied by a well-known method. Examples of such coating agents include hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.

在調製注射劑時，可使用pH調節劑、緩衝劑、穩定劑、等張化劑、局部麻醉劑等，並依據通常方法製造皮下、肌肉內及靜脈內用注射劑。When preparing injections, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc. can be used, and subcutaneous, intramuscular, and intravenous injections can be manufactured according to the usual methods.

pH調節劑及緩衝劑可列舉：檸檬酸鈉、乙酸鈉、磷酸鈉等。穩定劑可列舉：偏亞硫酸氫鈉、EDTA、硫乙二醇酸、硫乳酸等。局部麻醉劑可列舉：鹽酸普羅卡因(procaine hydrochloride)、鹽酸利度卡因(lidocaine hydrochloride)等。等張化劑可列舉：氯化鈉、葡萄糖、D-甘露糖醇、甘油等。Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, and glycerin.

此外，其他抗腫瘤劑之製劑亦包含該等之DDS(Drug Delivery System)製劑。例如，「紫杉醇」包含白蛋白懸濁型紫杉醇(例：Abraxane)及紫杉醇微粒(micelle)(例：NK105)等，「順鉑」包含順鉑微粒(例：NC-6004)等。In addition, other anti-tumor agent preparations also include these DDS (Drug Delivery System) preparations. For example, "paclitaxel" includes albumin suspension type paclitaxel (e.g., Abraxane) and paclitaxel microparticles (micelle) (e.g. NK105), etc., and "cisplatin" includes cisplatin microparticles (e.g. NC-6004) and the like.

於前述各投予單位形態中應摻合之聯苯化合物的量，雖係依擬適用其之患者的症狀，或其劑型等而非一定，但一般在每投予單位形態，希望於口服劑中設為0.05~1000mg，於注射劑中設為0.01~500mg，於栓劑中設為1~1000mg。Although the amount of biphenyl compound that should be blended in each of the aforementioned dosage unit forms depends on the symptoms of the patient to whom it is intended to be applied, or its dosage form, etc., it is generally in the form of each dosage unit. It is set to 0.05~1000mg in the medium, 0.01~500mg in the injection, and 1~1000mg in the suppository.

又，具有前述投予形態之聯苯化合物的每1日的投予量，雖依患者之症狀、體重、年齡、性別等而異而無法一概地決定，但聯苯化合物可設定成通常成人(體重50 kg)每1日為0.05~5000mg，且較佳為0.1~1000mg，且較佳係將其以1日1次或分成2~3次左右來投予。In addition, although the daily dosage of the biphenyl compound with the aforementioned administration form cannot be determined uniformly depending on the patient's symptoms, weight, age, sex, etc., the biphenyl compound can be set to a normal adult ( Body weight (50 kg) is 0.05-5000 mg per day, and preferably 0.1-1000 mg, and it is preferably administered once a day or divided into about 2 to 3 times.

實施例以下雖舉實施例來更為具體地說明本發明，但本發明當不因其等而受到任何限定。雖藉由實施例而充分地說明本發明，但習於此藝者當可理解各種變更或修飾皆可行。因此，只要如此的變更或修飾並未逸脫本發明之範圍時，其等皆包含在本發明中。Examples Although the following examples are given to explain the present invention more specifically, the present invention should not be limited in any way. Although the present invention is fully illustrated by the embodiments, those skilled in the art should understand that various changes or modifications are possible. Therefore, as long as such changes or modifications do not deviate from the scope of the present invention, they are all included in the present invention.

實施例所使用的各種試劑，只要無特別記載就是使用市售品。矽膠管柱層析法係使用Biotage製SNAP-ULTRA(註冊商標)Silica預充填管柱，或者鹼性矽膠管柱層析法係使用Biotage製KP-NH(註冊商標)預充填管柱。NMR光譜係使用AL400(400MHz；日本電子(JEOL))、Mercury 400(400MHz；Agilent Technologies)或500MHz Bruker AVANCE III HD NMR Spectrometer (500MHz；BURKER)型光譜儀，當在氘化溶劑中包含四甲基矽烷時，係使用四甲基矽烷作為內部基準，除此以外的情況則是使用NMR溶劑作為內部基準來進行測量，並以ppm表示全δ値。微波反應係使用Biotage公司製Initiator來進行。The various reagents used in the examples are commercially available products unless otherwise stated. The silica gel column chromatography method uses Biotage's SNAP-ULTRA (registered trademark) Silica pre-packed column, or the alkaline silica gel column chromatography uses Biotage's KP-NH (registered trademark) pre-packed column. NMR spectroscopy system uses AL400 (400MHz; JEOL), Mercury 400 (400MHz; Agilent Technologies) or 500MHz Bruker AVANCE III HD NMR Spectrometer (500MHz; BURKER) spectrometer, when tetramethylsilane is contained in the deuterated solvent When using tetramethylsilane as the internal reference, in other cases, the NMR solvent is used as the internal reference for measurement, and the total δ value is expressed in ppm. The microwave reaction system was performed using Initiator manufactured by Biotage Corporation.

又，LCMS光譜係使用Waters製ACQUITY SQD(四極型)並以下述條件測量。管柱：Waters製ACQUITY UPLC(註冊商標)BEH C18, 2.1×50mm, 1.7μmMS檢測：ESI positiveUV檢測：254及280nm管柱流速：0.5mL/min移動相：水/乙腈(0.1%甲酸)注射量：1μL增減率 (table 1)時間(分)　　　　　水 　　　　乙腈0　　　　　　　　95　　　　　　50.1　　　　　　　95　　　　　　52.1　　　　　　　 5　　　　　 953.0　　　　　　 停止In addition, the LCMS spectrum was measured under the following conditions using ACQUITY SQD (quadrupole type) manufactured by Waters. Column: ACQUITY UPLC (registered trademark) BEH C18 manufactured by Waters, 2.1×50mm, 1.7μm MS detection: ESI positiveUV detection: 254 and 280nm Column flow rate: 0.5mL/min Mobile phase: water/acetonitrile (0.1% formic acid) injection volume : 1μL change rate (table 1) time (min) acetonitrile water 50.1 95 52.1 095 953.0 5 stops

又，逆相分餾HPLC純化使用GILSON公司製分餾系統且以下述條件實施。管柱：Waters製 Xselect CSH Prep C18 5μm OBD (19×50mm)＋(19×100mm)UV檢測：254nm管柱流速：18mL/min移動相：水/乙腈(0.1%甲酸)注射量：0.1-0.5mLIn addition, the reverse phase fractionation HPLC purification was carried out under the following conditions using a fractionation system manufactured by GILSON Corporation. Column: Waters Xselect CSH Prep C18 5μm OBD (19×50mm) + (19×100mm) UV detection: 254nm Column flow rate: 18mL/min Mobile phase: water/acetonitrile (0.1% formic acid) Injection volume: 0.1-0.5 mL

縮寫的意義係如以下所示。The meaning of the abbreviations is as follows.

s：單峰d：雙峰t：三峰q：四峰dd：雙重　雙峰dt：雙重　三峰td：三重　雙峰tt：三重　三峰ddd：雙重　雙重　雙峰ddt：雙重　雙重　三峰dtd：雙重　三重　雙峰tdd：三重　雙重　雙峰m：多重峰br：寬峰brs：寬單峰THF：四氫呋喃DMF：N,N-二甲基甲醯胺DME：1,2-二甲氧乙烷DMSO：二甲基亞碸HATU：O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基六脲鎓六氟磷酸鹽TEA：三乙基胺WSC HCl：1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺鹽酸鹽t-BuOH：第三丁醇DMAP：N,N-二甲基胺基吡啶Pd(PPh3 )4 ：肆(三苯基膦)鈀(0)Pd(dba)2 ：雙(二亞苯甲基丙酮)鈀(0)PCy3 ：三環己基膦TFA：三氟乙酸Pd(OAc)2 ：乙酸鈀KOAc：乙酸鉀PdCl2 (dppf) ：[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物PdCl2 (dppf)CH2 Cl2 ：[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物　二氯甲烷錯合物DMEAD：二-2-甲氧基乙基偶氮二羧酸酯PPh3 ：三苯基膦DMA：二甲基乙醯胺MeMgBr：甲基溴化鎂EtMgBr：乙基溴化鎂MTBE：甲基第三丁基醚DCM：二氯甲烷Boc2 O：二碳酸二第三丁酯NBS：N-溴琥珀醯亞胺X-phos：2-二環己基膦基-2’,4’,6’-三異丙基聯苯MeOH：甲醇EtOH：乙醇IPE：二異丙基醚TBAF：四丁基氟化銨Pd2 (dba)3 ：参(二亞苯甲基丙酮)二鈀(0)PdCl2 (PPh3 )2 ：氯化鈀雙三苯基膦S-Phos：2-二環己基膦-2,6-二甲氧基聯苯HOBt：1-羥基苯并三唑Pd/C：碳載持鈀NMP：N-甲基-2-吡咯啶酮。s: single peak d: double peak t: triple peak q: four peak dd: double double peak dt: double triple peak td: triple double peak tt: triple triple peak ddd: double double double peak ddt: double double triple peak dtd: double triple double peak tdd: triple double doublet m: multiplet br: broad peak brs: broad single peak THF: tetrahydrofuran DMF: N,N-dimethylformamide DME: 1,2-dimethoxyethane DMSO: dimethyl Sulfide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate TEA: Triethylamine WSC HCl: 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride t-BuOH: tertiary butanol DMAP: N,N-dimethylaminopyridine Pd(PPh 3 ) 4 : Four (triphenylphosphine) palladium(0)Pd(dba) 2 : Bis(dibenzylideneacetone)palladium(0)PCy 3 : Tricyclohexylphosphine TFA: Trifluoroacetic acid Pd(OAc) 2 : Palladium acetate KOAc: Potassium acetate PdCl 2 (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PdCl 2 (dppf)CH 2 Cl 2 : [1 ,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex DMEAD: di-2-methoxyethyl azodicarboxylate PPh 3 : three Phenylphosphine DMA: Dimethylacetamide MeMgBr: Methylmagnesium bromide EtMgBr: Ethylmagnesium bromide MTBE: Methyl tertiary butyl ether DCM: Dichloromethane Boc 2 O: Di-tertiary butyl dicarbonate NBS: N-bromosuccinimide X-phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl MeOH: Methanol EtOH: Ethanol IPE: Diisopropyl ether TBAF : Tetrabutylammonium fluoride Pd 2 (dba) 3 : ginseng (dibenzylidene acetone)dipalladium (0)PdCl 2 (PPh 3 ) 2 : palladium chloride bistriphenylphosphine S-Phos: 2- Dicyclohexylphosphine-2,6-dimethoxybiphenyl HOBt: 1-hydroxybenzotriazole Pd/C: Carbon-supported palladium NMP: N-methyl-2-pyrrolidone.

實施例1　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(對甲苯基)苯基]苯甲腈之合成　(步驟1)將3-溴-4-氯-苯甲酸 19g溶解於DMF 160mL中。於25℃添加DMAP 20g、WSC HCl 31g，接著添加t-BuOH 38mL並於室溫徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　3-溴-4-氯-苯甲酸酯。Example 1 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile (Step 1) -19 g of chloro-benzoic acid was dissolved in 160 mL of DMF. 20 g of DMAP and 31 g of WSC HCl were added at 25°C, and then 38 mL of t-BuOH was added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-bromo-4-chloro-benzoic acid ester.

(步驟2)將前述步驟1所得到的第三丁基　3-溴-4-氯-苯甲酸酯 1.3g溶解於1,4-二噁烷 8.7mL中。於室溫添加(4-氰基苯基)硼酸768mg、Pd(PPh3)4 151mg、2M Na2CO3水溶液 5.4mL，於微波反應裝置中在120℃下攪拌反應液30分鐘。減壓濃縮反應液後，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　4-氯-3-(4-氰基苯基)苯甲酸酯。(Step 2) Dissolve 1.3 g of the tertiary butyl "3-bromo-4-chloro-benzoic acid ester obtained in the aforementioned step 1 in 8.7 mL of 1,4-dioxane. 768 mg of (4-cyanophenyl)boronic acid, 151 mg of Pd(PPh3)4, and 5.4 mL of 2M Na2CO3 aqueous solution were added at room temperature, and the reaction solution was stirred at 120°C for 30 minutes in a microwave reactor. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 4-chloro-3-(4-cyanophenyl)benzene Formate.

(步驟3)將前述步驟2所得到的第三丁基　4-氯-3-(4-氰基苯基)苯甲酸酯 1.1g溶解於1,4-二噁烷17mL中。於室溫添加對甲苯基硼酸932mg、Pd(dba)2 157mg、磷酸三鉀 1.5g、1M PCy3　THF溶液 0.57mL。於微波反應裝置中在160℃下攪拌反應液30分鐘。添加氯仿，濾別不溶物，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於TFA 2mL中。蒸餾去除溶劑。添加乙酸乙酯，並以水、飽和食鹽水依序洗淨。以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑，而得到3-(4-氰基苯基)-4-(對甲苯基)苯甲酸。(Step 3) 1.1 g of tert-butyl 4-chloro-3-(4-cyanophenyl) benzoate obtained in step 2 above was dissolved in 17 mL of 1,4-dioxane. At room temperature, 932 mg of p-tolyl boronic acid, 2 157 mg of Pd(dba), 1.5 g of tripotassium phosphate, and 0.57 mL of a 1M PCy3"THF solution were added. The reaction solution was stirred at 160°C for 30 minutes in a microwave reaction device. Add chloroform, filter out the insoluble matter, and distill to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in TFA 2mL. The solvent is removed by distillation. Add ethyl acetate, and wash with water and saturated saline in this order. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off to obtain 3-(4-cyanophenyl)-4-(p-tolyl)benzoic acid.

(步驟4)將前述步驟3所得到的3-(4-氰基苯基)-4-(對甲苯基)苯甲酸 10mg、第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯 6mg、HATU 24mg溶解於THF 0.5mL中。於室溫添加TEA 0.013mL，於50℃徹夜攪拌。減壓濃縮反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 4) Combine 10 mg of 3-(4-cyanophenyl)-4-(p-tolyl)benzoic acid and tertiary butyl N-((3S)-pyrrolidin-3-yl ] 6 mg of carbamate and 24 mg of HATU were dissolved in 0.5 mL of THF. 0.013 mL of TEA was added at room temperature, and stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4 -(P-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟5)將前述步驟4所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzyl)pyrrolidine obtained in the aforementioned step 4 15 mg of -3-yl] carbamate was dissolved in 0.3 mL of TFA, and after confirming the progress of the reaction by LCMS, it was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例2　4-[5-[(3S)-3-胺基吡咯啶-1-硫代羰基]-2-(對甲苯基)苯基]苯甲腈之合成將實施例1(步驟5)所得到的4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(對甲苯基)苯基]苯甲腈　6mg溶解於THF 0.8mL中。於室溫添加LAWESSON’S　REAGENT　3.8mg，於室溫攪拌30分鐘。添加氯仿，以碳酸氫鈉水分液，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 2 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-thiocarbonyl]-2-(p-tolyl)phenyl]benzonitrile Example 1 (Step 5) 6 mg of the obtained 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile was dissolved in 0.8 mL of THF. 3.8 mg of LAWESSON’S "REAGENT" was added at room temperature, and stirred at room temperature for 30 minutes. Chloroform was added, the organic layer was dried with anhydrous sodium sulfate with sodium bicarbonate aqueous solution, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例3　4-[5-(4-胺基哌啶-1-羰基)-2-(對甲苯基)苯基]苯甲腈之合成(步驟1)將實施例1(步驟3)所得到的3-(4-氰基苯基)-4-(對甲苯基)苯甲酸 20mg溶解於THF 1mL中。於室溫添加第三丁基　N-(4-哌啶基)胺甲酸酯 13mg、HATU 49mg、TEA 0.027mL，於50℃徹夜攪拌。減壓濃縮反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[1-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]-4-哌啶基]胺甲酸酯。(步驟2)將前述步驟1所得到的第三丁基　N-[1-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]-4-哌啶基]胺甲酸酯 30mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 3 "Synthesis of 4-[5-(4-aminopiperidine-1-carbonyl)-2-(p-tolyl)phenyl] benzonitrile (Step 1) Obtained from Example 1 (Step 3) 20 mg of 3-(4-cyanophenyl)-4-(p-tolyl)benzoic acid was dissolved in 1 mL of THF. 13 mg of tert-butyl "N-(4-piperidyl) carbamate, 49 mg of HATU, and 0.027 mL of TEA were added at room temperature, and the mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[1-[3-(4-cyanophenyl)-4-(p-toluene) Yl)benzoyl]-4-piperidinyl]carbamate. (Step 2) Combine the tertiary butyl N-[1-[3-(4-cyanophenyl)-4-(p-tolyl)benzyl]-4-piperidinyl obtained in step 1 above ] 30 mg of carbamate was dissolved in 0.3 mL of TFA, and after the progress of the reaction was confirmed by LCMS, it was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例4　4-[5-(2,8-二氮雜螺[3.5]壬烷-2-羰基)-2-(對甲苯基)苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用第三丁基　2,8-二氮雜螺[3.5]壬烷-8-羧酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 4 The synthesis of 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-(p-tolyl)phenyl]benzonitrile is based on Example 1 (Step 1 ~5) shall prevail, by using tertiary butyl 2,8-diazaspiro[3.5]nonane-8-carboxylate hydrochloride instead of tertiary butyl N-[(3S)-pyrrolidine -3-yl]carbamate to obtain the title compound.

實施例5　4-[5-(2,7-二氮雜螺[3.4]辛烷-7-羰基)-2-(對甲苯基)苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用第三丁基　2,7-二氮雜螺[3.4]辛烷-2-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 5 The synthesis of 4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-(p-tolyl)phenyl]benzonitrile was used in Example 1 (Step 1 ~5) shall prevail, by using tertiary butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tertiary butyl N-[(3S)-pyrrolidine-3- Group] carbamate to obtain the title compound.

實施例6　4-[5-(3,8-二氮雜螺[4.4]壬烷-8-羰基)-2-(對甲苯基)苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用第三丁基　3,8-二氮雜螺[4.4]壬烷-8-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 6 The synthesis of 4-[5-(3,8-diazaspiro[4.4]nonane-8-carbonyl)-2-(p-tolyl)phenyl]benzonitrile was used in Example 1 (Step 1 ~5) shall prevail, by using tertiary butyl 3,8-diazaspiro[4.4]nonane-8-carboxylate instead of tertiary butyl N-[(3S)-pyrrolidine-3- Group] carbamate to obtain the title compound.

實施例7　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(對甲苯基)苯基]苯甲腈之合成(步驟1)將3-溴-4-氯-苯甲酸 500mg溶解於DMA 5.3mL中。於室溫添加HATU 1g、TEA 0.59mL，接著添加第三丁基　N-[(3-外)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 480mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-(3-溴-4-氯-苯甲醯基)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 7 "4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(p-tolyl)phenyl]benzyl Synthesis of Nitrile (Step 1) Dissolve 500 mg of 3-bromo-4-chloro-benzoic acid in 5.3 mL of DMA. Add 1 g of HATU and 0.59 mL of TEA at room temperature, and then add 480 mg of tert-butyl N-[(3-exo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate. Stir at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-exo)-8-(3-bromo-4-chloro-benzyl) (Acidyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-外)-8-(3-溴-4-氯-苯甲醯基)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 200mg溶解於1,4-二噁烷2.3mL中。於室溫添加(4-氰基苯基)硼酸60mg、Pd(PPh3)4 16mg、2M Na2CO3水溶液 1.1mL，於微波反應裝置中在120℃下攪拌反應液30分鐘。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-[4-氯-3-(4-氰基苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3-exo)-8-(3-bromo-4-chloro-benzyl)-8-azabicyclo[3.2.1 200 mg of ]octan-3-yl] carbamate was dissolved in 2.3 mL of 1,4-dioxane. 60 mg of (4-cyanophenyl)boronic acid, 16 mg of Pd(PPh3)4, and 1.1 mL of 2M Na2CO3 aqueous solution were added at room temperature, and the reaction solution was stirred at 120°C for 30 minutes in a microwave reactor. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-外)-8-[4-chloro-3- (4-Cyanophenyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3-外)-8-[4-氯-3-(4-氰基苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於1,4-二噁烷0.322mL中。於室溫添加對甲苯基硼酸5.3mg、Pd(dba)2 0.93mg、1M PCy3 THF溶液 0.003mL、磷酸三鉀 21mg，於微波反應裝置中在160℃下攪拌反應液30分鐘。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 3) The tertiary butyl N-[(3-exo)-8-[4-chloro-3-(4-cyanophenyl)benzyl]-8-nitrogen obtained in step 2 above 15 mg of heterobicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.322 mL of 1,4-dioxane. 5.3 mg of p-tolylboronic acid, 0.93 mg of Pd(dba)2, 0.003 mL of 1M PCy 3 THF solution, and 21 mg of tripotassium phosphate were added at room temperature, and the reaction solution was stirred at 160° C. for 30 minutes in a microwave reactor. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-外)-8-[3-(4-cyanide) Phenyl)-4-(p-tolyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基苯基)-4-(對甲苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3-exo)-8-[3-(4-cyanophenyl)-4-(p-tolyl)benzyl] obtained in the aforementioned step 3 15 mg of -8-azabicyclo[3.2.1]octan-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例8　4-[5-[(3S)-3-胺基-3-甲基-吡咯啶-1-羰基]-2-(對甲苯基)苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用第三丁基　N-[(3S)-3-甲基吡咯啶-3-基]胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 8 "Synthesis of 4-[5-[(3S)-3-amino-3-methyl-pyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile Take Example 1 (Steps 1~5) shall prevail, by using tertiary butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate instead of tertiary butyl N-[(3S) -Pyrrolidin-3-yl] carbamate to obtain the title compound.

實施例9　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2-氯-4-甲基-苯基)苯基]苯甲腈之合成(步驟1)將3-溴-4-氯-苯甲酸 10g溶解於DMA 85mL中。於室溫添加HATU 24g、TEA 12mL，接著添加第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯 8.7g，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-(3-溴-4-氯-苯甲醯基)吡咯啶-3-基]胺甲酸酯。Example 9 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-chloro-4-methyl-phenyl)phenyl]benzonitrile (step 1) Dissolve 10 g of 3-bromo-4-chloro-benzoic acid in 85 mL of DMA. 24 g of HATU and 12 mL of TEA were added at room temperature, and then 8.7 g of tert-butyl "N-[(3S)-pyrrolidin-3-yl]carbamate was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-(3-bromo-4-chloro-benzyl) ) Pyrrolidin-3-yl] carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-(3-溴-4-氯-苯甲醯基)吡咯啶-3-基]胺甲酸酯 2.2g溶解於1,4-二噁烷13.6mL中。於室溫添加4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲腈　1.5g、Pd(PPh3 )4 189mg、2M Na2CO3水溶液 6.8mL，於微波反應裝置中在120℃下攪拌反應液30分鐘。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-(3-bromo-4-chloro-benzoyl)pyrrolidin-3-yl)carbamate obtained in the aforementioned step 1 is 2.2 g was dissolved in 13.6 mL of 1,4-dioxane. Add 1.5 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and Pd(PPh 3 ) 4 189 mg at room temperature , 6.8 mL of 2M Na2CO3 aqueous solution, stir the reaction solution in a microwave reaction device at 120°C for 30 minutes. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanobenzene) Yl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 500mg溶解於1,4-二噁烷9.8mL中。於室溫添加Pd(OAc)2 26mg、KOAc 346mg、雙(品納可基)二硼烷(Bis(pinacolato)diboran) 596mg、Silica-SMAP(和光純藥製) 150mg，於160℃徹夜攪拌。以矽藻土過濾，減壓濃縮濾液。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 3) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzyl]pyrrolidin-3-yl obtained in step 2 above ] 500 mg of carbamate was dissolved in 9.8 mL of 1,4-dioxane. Pd(OAc) 2 26 mg, KOAc 346 mg, Bis (pinacolato) diboran (Bis (pinacolato) diboran) 596 mg, and Silica-SMAP (manufactured by Wako Pure Chemical Industries, Ltd.) 150 mg were added at room temperature, and stirred overnight at 160°C. It was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟4)前述步驟3所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg、1-溴-2-氯-4-甲基-苯 12mg、Pd(PPh3 )4 1.7mg懸浮於1,4-二噁烷1.5mL中。於室溫添加2M Na2 CO3 水溶液 0.7mL，於120℃攪拌30分鐘。過濾反應液後，蒸餾去除溶劑，而得到第三丁基　N-[(3S)-1-[4-(2-氯-4-甲基-苯基)-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 4) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate 15mg, 1-bromo-2-chloro-4-methyl-benzene 12 mg and 1.7 mg of Pd(PPh 3 ) 4 were suspended in 1.5 mL of 1,4-dioxane. 0.7 mL of 2M Na 2 CO 3 aqueous solution was added at room temperature, and stirred at 120°C for 30 minutes. After filtering the reaction liquid, the solvent was distilled off to obtain tertiary butyl N-[(3S)-1-[4-(2-chloro-4-methyl-phenyl)-3-(4-cyanophenyl) )Benzoyl]pyrrolidin-3-yl]carbamate.

(步驟5)將前述步驟4所得到的第三丁基　N-[(3S)-1-[4-(2-氯-4-甲基-苯基)-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The tertiary butyl N-[(3S)-1-[4-(2-chloro-4-methyl-phenyl)-3-(4-cyanophenyl) obtained in the aforementioned step 4 ) 15 mg of benzyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例10　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(3-氯-4-甲基-苯基)苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用4-溴-2-氯-1-甲基-苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 10 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-chloro-4-methyl-phenyl)phenyl]benzonitrile for implementation Example 9 (Steps 1 to 5) shall prevail. By using 4-bromo-2-chloro-1-methyl-benzene instead of 1-bromo-2-chloro-4-methyl-benzene, the title compound is obtained.

實施例11　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[3-氟-4-(三氟甲基)苯基]苯基]苯甲腈之合成　以實施例9(步驟1~5)為準，藉由使用4-溴-2-氟-1-(三氟甲基)苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 11 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[3-fluoro-4-(trifluoromethyl)phenyl]phenyl]benzonitrile The synthesis is based on Example 9 (steps 1 to 5), by using 4-bromo-2-fluoro-1-(trifluoromethyl)benzene instead of 1-bromo-2-chloro-4-methyl-benzene , And get the title compound.

實施例12　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-甲基-2-硝基-苯基)苯基]苯甲腈之合成(步驟1)添加實施例9(步驟2)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg、4-甲基-2-硝基苯基硼酸,　品納可(pinacol)　酯 18mg、Pd(dba)2 1.6mg、1M PCy3 THF溶液 0.003mL、磷酸三鉀 15mg，於微波反應裝置中在160℃下攪拌反應液30分鐘。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4-甲基-2-硝基-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 12 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-methyl-2-nitro-phenyl)phenyl]benzonitrile ( Step 1) Add the tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzyl]pyrrolidine obtained in Example 9 (Step 2) 3-yl) carbamate 15mg, 4-methyl-2-nitrophenylboronic acid, pinacol ester 18mg, Pd(dba) 2 1.6mg, 1M PCy 3 THF solution 0.003mL, triphosphate Potassium 15mg, the reaction solution was stirred at 160°C for 30 minutes in a microwave reaction device. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanobenzene) Yl)-4-(4-methyl-2-nitro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4-甲基-2-硝基-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 10mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-methyl-2-nitro-benzene 10 mg of benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例13　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(二氟甲基)苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-溴-4-(二氟甲基)苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 13 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(difluoromethyl)phenyl]phenyl]benzonitrile 9 (Steps 1 to 5) shall prevail. By using 1-bromo-4-(difluoromethyl)benzene instead of 1-bromo-2-chloro-4-methyl-benzene, the title compound is obtained.

實施例14　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(三氟甲基)苯基]苯基]苯甲腈之合成　以實施例12(步驟1~2)為準，藉由使用[4-(三氟甲基)苯基]硼酸來代替4-甲基-2-硝基苯基硼酸　品納可　酯，而得到標題化合物。Example 14 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(trifluoromethyl)phenyl]phenyl]benzonitrile 12 (Steps 1~2) shall prevail, and the title compound can be obtained by using [4-(trifluoromethyl)phenyl]boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacolinate.

實施例15　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2-氟-4-甲基-苯基)苯基]苯甲腈之合成　(步驟1)將實施例9(步驟2)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 1.7g溶解於1,4-二噁烷20mL中。於室溫添加(2-氟-4-甲基-苯基)硼酸980mg、Pd(dba)2 110mg、1M PCy3 THF溶液 0.4mL、磷酸三鉀 2.5g，於微波反應裝置中在160℃下攪拌反應液45分鐘。以NH矽膠純化，並以甲醇/乙酸乙酯洗淨，蒸餾去除溶劑，而得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(2-氟-4-甲基-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 15 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-fluoro-4-methyl-phenyl)phenyl]benzonitrile (Step 1) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzyl]pyrrolidine-3 obtained in Example 9 (Step 2) 1.7 g of -yl] carbamate was dissolved in 20 mL of 1,4-dioxane. Add 980 mg of (2-fluoro-4-methyl-phenyl)boronic acid, 110 mg of Pd(dba) 2 , 0.4 mL of 1M PCy 3 THF solution, and 2.5 g of tripotassium phosphate at room temperature, and in a microwave reactor at 160°C The reaction solution was stirred for 45 minutes. Purified with NH silica gel, washed with methanol/ethyl acetate, and distilled to remove the solvent to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(2) -Fluoro-4-methyl-phenyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(2-氟-4-甲基-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 1.7g溶解於TFA 44mL中，攪拌10分鐘。蒸餾去除溶劑，藉由逆相HPLC(移動相：水/乙腈)純化，而得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(2-fluoro-4-methyl-phenyl) obtained in the aforementioned step 1 ) Benzyl]pyrrolidin-3-yl]carbamate 1.7 g was dissolved in 44 mL of TFA, and stirred for 10 minutes. The solvent was distilled off and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例16　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(對甲苯基)苯基]-2-氟-苯甲腈之合成(步驟1)將實施例9(步驟1)所得到的第三丁基　N-[(3S)-1-(3-溴-4-氯-苯甲醯基)吡咯啶-3-基]胺甲酸酯 14g溶解於1,4-二噁烷87mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸6.3g、Pd(PPh3 )4 1.2g、2M Na2 CO3 水溶液 44mL，於90℃徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 16 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]-2-fluoro-benzonitrile (Step 1) Dissolve 14 g of the tertiary butyl N-[(3S)-1-(3-bromo-4-chloro-benzoyl)pyrrolidin-3-yl]carbamate obtained in Example 9 (Step 1) In 87mL of 1,4-dioxane. 6.3 g of (4-cyano-3-fluoro-phenyl)boronic acid, 1.2 g of Pd(PPh 3 ) 4 , and 44 mL of 2M Na 2 CO 3 aqueous solution were added at room temperature, and the mixture was stirred at 90°C overnight. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyano- 3-Fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 48mg溶解於1,4-二噁烷0.5mL中。於室溫添加對甲苯基硼酸29mg、Pd(dba)2 3.1mg、1M PCy3 THF溶液 0.005mL、磷酸三鉀 68mg，於微波反應裝置中在160℃下攪拌反應液45分鐘。以NH矽膠純化，並以甲醇/乙酸乙酯洗淨，蒸餾去除溶劑，而得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzyl]pyrrole obtained in the previous step 1 48 mg of pyridin-3-yl] carbamate was dissolved in 0.5 mL of 1,4-dioxane. P-tolyl boronic acid 29 mg, Pd(dba) 2 3.1 mg, 1M PCy 3 THF solution 0.005 mL, and tripotassium phosphate 68 mg were added at room temperature, and the reaction solution was stirred at 160° C. for 45 minutes in a microwave reactor. Purified with NH silica gel, washed with methanol/ethyl acetate, and distilled to remove the solvent to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟3)對前述步驟2所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 48mg添加TFA 1.2mL，攪拌10分鐘。蒸餾去除溶劑，藉由逆相HPLC(移動相：水/乙腈)純化以得到標題化合物。(Step 3) To the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl)benzyl obtained in step 2 above 1.2 mL of TFA was added to 48 mg of pyrrolidin-3-yl]carbamate, and the mixture was stirred for 10 minutes. The solvent was distilled off and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例17　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(對甲苯基)苯基]-2-氟-苯甲腈之合成(步驟1)將3-溴-4-氯-苯甲酸 700mg溶解於THF 15mL中。於室溫添加HATU 1.2g、TEA 0.83mL，接著添加第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 700mg，於50℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-(3-溴-4-氯-苯甲醯基)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 17 "4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(p-tolyl)phenyl]-2 -Synthesis of fluoro-benzonitrile (Step 1) 700 mg of 3-bromo-4-chloro-benzoic acid was dissolved in 15 mL of THF. At room temperature, 1.2 g of HATU and 0.83 mL of TEA were added, followed by 700 mg of tert-butyl N-[(3-internal)-8-azabicyclo[3.2.1]octan-3-yl]carbamate, Stir at 50°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-内)-8-(3-bromo-4- Chloro-benzyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基-N-[(3-內)-8-(3-溴-4-氯-苯甲醯基)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 1.2g溶解於1,4-二噁烷6.7mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸461mg、PdCl2 (dppf)　58mg、2M Na2 CO3 水溶液 3.3mL，於95℃徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 2) The tertiary butyl-N-((3-internal)-8-(3-bromo-4-chloro-benzyl)-8-azabicyclo(3.2. 1] 1.2 g of octane-3-yl] carbamate was dissolved in 6.7 mL of 1,4-dioxane. 461 mg of (4-cyano-3-fluoro-phenyl)boronic acid, 58 mg of PdCl 2 (dppf), and 3.3 mL of 2M Na 2 CO 3 aqueous solution were added at room temperature, and the mixture was stirred at 95°C overnight. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-internal)-8-[4-chloro-3-(4-cyanide) 3-fluoro-phenyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3-內)-8-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 17mg溶解於1,4-二噁烷0.5mL中。於室溫下添加對甲苯基硼酸9.6mg、Pd(dba)2 1.6mg、磷酸三鉀 15mg、1M PCy3 THF溶液 0.004mL，於微波反應裝置中在160℃攪拌30分鐘。以NH矽膠過濾反應液、蒸餾去除濾液之溶劑，而得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(對甲苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 3) The tertiary butyl N-[(3-internal)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzyl group obtained in the aforementioned step 2 17 mg of ]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.5 mL of 1,4-dioxane. 9.6 mg of p-tolylboronic acid, 1.6 mg of Pd(dba) 2 , 15 mg of tripotassium phosphate, and 0.004 mL of 1M PCy 3 THF solution were added at room temperature, and the mixture was stirred at 160° C. for 30 minutes in a microwave reactor. The reaction solution was filtered with NH silica gel, and the solvent of the filtrate was distilled off to obtain tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-( P-tolyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(對甲苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl) obtained in the aforementioned step 3 15 mg of benzyl]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例18　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(1-甲基吲哚-5-基)苯基]-2-氟-苯甲腈之合成(步驟1)將實施例7(步驟1)所得到的第三丁基　N-[(3-外)-8-(3-溴-4-氯-苯甲醯基)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 300mg溶解於1,4-二噁烷1.7mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸123mg、PdCl2 (dppf)　17mg、2M Na2 CO3 水溶液 0.85mL，在微波反應裝置中於120℃攪拌反應液30分鐘。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 18 4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(1-methylindole-5- Synthesis of phenyl)-2-fluoro-benzonitrile (step 1) The tertiary butyl N-[(3-exo)-8-(3-bromo- 300 mg of 4-chloro-benzyl)-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 1.7 mL of 1,4-dioxane. 123 mg of (4-cyano-3-fluoro-phenyl)boronic acid, 17 mg of PdCl 2 (dppf), and 0.85 mL of 2M Na 2 CO 3 aqueous solution were added at room temperature, and the reaction solution was stirred at 120° C. for 30 minutes in a microwave reactor. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-外)-8-[4-chloro-3-(4-cyanide) 3-fluoro-phenyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-外)-8-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 10mg溶解於1,4-二噁烷0.5mL中。於室溫添加(1-甲基吲哚-5-基)硼酸7.2mg、Pd(dba)2 0.9mg、磷酸三鉀 8.8mg、1M PCy3 THF溶液 0.002mL，在微波反應裝置中於160℃攪拌反應液30分鐘。以NH矽膠過濾反應液，蒸餾去除濾液之溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(1-甲基吲哚-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3-exo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzyl 10 mg of ]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.5 mL of 1,4-dioxane. Add (1-methylindol-5-yl)boronic acid 7.2mg, Pd(dba) 2 0.9mg, tripotassium phosphate 8.8mg, 1M PCy 3 THF solution 0.002mL at room temperature, in a microwave reactor at 160℃ The reaction solution was stirred for 30 minutes. The reaction solution was filtered with NH silica gel, and the solvent of the filtrate was removed by distillation. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-外)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-(1-methylindol-5-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(1-甲基吲哚-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(1-methyl 15 mg of indol-5-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate was dissolved in 0.3mL of TFA, and the progress of the reaction was confirmed by LCMS. Concentrate under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例19　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(對甲苯基)苯基]-2,6-二氟-苯甲腈之合成(步驟1)將4-溴-3-氯-苯甲酸 2g溶解於DMA 17mL中。於室溫添加HATU 4.8g、TEA 2.4mL，接著添加第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯 1.7g，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-(4-溴-3-氯-苯甲醯基)吡咯啶-3-基]胺甲酸酯。Example 19 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]-2,6-difluoro-benzonitrile (Step 1) Dissolve 2 g of 4-bromo-3-chloro-benzoic acid in 17 mL of DMA. 4.8 g of HATU and 2.4 mL of TEA were added at room temperature, followed by addition of 1.7 g of tertiary butyl "N-[(3S)-pyrrolidin-3-yl]carbamate, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-(4-bromo-3-chloro-benzyl) ) Pyrrolidin-3-yl] carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-(4-溴-3-氯-苯甲醯基)吡咯啶-3-基]胺甲酸酯溶解於1,4-二噁烷10.6mL中。於室溫添加Pd(PPh3 )4 147mg、2M Na2 CO3 水溶液 5.3mL、對甲苯基硼酸693mg，於微波反應裝置中在120℃攪拌反應液30分鐘。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-氯-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) Dissolve the tertiary butyl N-[(3S)-1-(4-bromo-3-chloro-benzoyl)pyrrolidin-3-yl)carbamate obtained in step 1 above In 1,4-dioxane 10.6mL. Pd(PPh 3 ) 4 147 mg, 2M Na 2 CO 3 aqueous solution 5.3 mL, and p-tolyl boronic acid 693 mg were added at room temperature, and the reaction solution was stirred at 120° C. for 30 minutes in a microwave reactor. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-chloro-4-(p-tolyl)benzene Formyl]pyrrolidin-3-yl]carbamate.

(步驟3)　將前述步驟2所得到的第三丁基　N-[(3S)-1-[3-氯-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 666mg溶解於1,4-二噁烷16mL中。於室溫添加Pd(OAc)2 36mg、KOAc 473mg、雙(品納可基)二硼烷815mg、1M PCy3 THF溶液 0.24mL，經脫氣氮取代後，於80℃徹夜攪拌。以矽藻土過濾反應液，蒸餾去除濾液之溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[4-(對甲苯基)-3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 3) The tertiary butyl N-[(3S)-1-[3-chloro-4-(p-tolyl)benzyl]pyrrolidin-3-yl]carbamate obtained in the aforementioned step 2 666 mg of acid ester was dissolved in 16 mL of 1,4-dioxane. 36 mg of Pd(OAc) 2 , 473 mg of KOAc, 815 mg of bis(pinnacyl) diborane, and 0.24 mL of 1M PCy 3 THF solution were added at room temperature. After substitution with degassed nitrogen, the mixture was stirred overnight at 80°C. The reaction solution was filtered with celite, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[4-(p-tolyl)-3-(4) ,4,5,5-Tetramethyl-1,3,2-dioxole-2-yl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3S)-1-[4-(對甲苯基)-3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg、4-溴-2,6-二氟-苯甲腈　12.9mg、Pd(PPh3 )4 1.7mg懸浮於1,4-二噁烷1.5mL中。於室溫添加2M Na2CO3水溶液 0.7mL，於微波反應裝置中在120℃攪拌反應液30分鐘。過濾反應液之後蒸餾去除溶劑，而得到第三丁基　N-[(3S)-1-[3-(4-氰基-3,5-二氟-苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 4) The tertiary butyl N-[(3S)-1-[4-(p-tolyl)-3-(4,4,5,5-tetramethyl-1, 3,2-Dioxolpan-2-yl)benzyl)pyrrolidin-3-yl)carbamate 15mg, 4-bromo-2,6-difluoro-benzonitrile 12.9mg , Pd(PPh 3 ) 4 1.7 mg was suspended in 1.5 mL of 1,4-dioxane. 0.7 mL of 2M Na2CO3 aqueous solution was added at room temperature, and the reaction solution was stirred at 120°C for 30 minutes in a microwave reaction device. After filtering the reaction liquid, the solvent was distilled off to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3,5-difluoro-phenyl)-4-(p-tolyl) Benzyl]pyrrolidin-3-yl]carbamate.

(步驟5)將前述步驟4所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3,5-二氟-苯基)-4-(對甲苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The tertiary butyl N-((3S)-1-[3-(4-cyano-3,5-difluoro-phenyl)-4-(p-tolyl) obtained in the aforementioned step 4 ) 15 mg of benzyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例20　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　(步驟1)將1-溴-2-氟-4-(2-甲氧基乙基)苯 4.5g懸浮於1,4-二噁烷48mL中並攪拌。添加雙(品納可基)二硼烷7.4g、KOAc 3.8g、PdCl2 (dppf) 0.71g，於90℃徹夜攪拌。添加乙酸乙酯，進行矽藻土過濾後，以水、飽和食鹽水依序洗淨濾液，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到2-[2-氟-4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷。Example 20 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]- Synthesis of 2-fluoro-benzonitrile (Step 1) 4.5 g of 1-bromo-2-fluoro-4-(2-methoxyethyl)benzene was suspended in 48 mL of 1,4-dioxane and stirred. Add 7.4 g of bis(pinnacyl) diborane, 3.8 g of KOAc, and 0.71 g of PdCl 2 (dppf), and stir at 90°C overnight. After adding ethyl acetate and performing Celite filtration, the filtrate was washed sequentially with water and saturated brine, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 2-[2-fluoro-4-(2-methoxyethyl)phenyl]-4,4, 5,5-Tetramethyl-1,3,2-dioxolane.

(步驟2)將實施例16(步驟1)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 150mg、前述步驟1所得到的2-[2-氟-4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷　189mg、Pd(dba)2 15mg、磷酸三鉀 144mg、1M PCy3 THF溶液 0.034mL溶解於1,4-二噁烷3.8mL中。於微波反應裝置中在160℃下攪拌反應液45分鐘。以NH矽膠過濾反應液，蒸餾去除濾液之溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzyl obtained in Example 16 (Step 1) Amino]pyrrolidin-3-yl]carbamate 150mg, 2-[2-fluoro-4-(2-methoxyethyl)phenyl]-4,4,5 obtained in step 1 above, 5-tetramethyl-1,3,2-dioxolane 189mg, Pd(dba) 2 15mg, tripotassium phosphate 144mg, 1M PCy 3 THF solution 0.034mL dissolved in 1,4-dioxane 3.8 mL in. The reaction solution was stirred at 160°C for 45 minutes in a microwave reaction device. The reaction solution was filtered with NH silica gel, and the solvent of the filtrate was removed by distillation. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4 -[2-Fluoro-4-(2-methoxyethyl)phenyl]benzyl]pyrrolidin-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 150mg溶解於TFA 10mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[2-fluoro-4-(2-methoxy 150 mg of phenylethyl)phenyl]benzyl]pyrrolidin-3-yl]carbamate was dissolved in 10 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例21　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(2-氟-4-甲基-苯基)苯基]-2-氟-苯甲腈之合成以實施例17(步驟1~4)為準，藉由使用(2-氟-4-甲基-苯基)硼酸對甲苯基硼酸，而得到標題化合物。Example 21 "4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-fluoro-4-methyl- The synthesis of (phenyl)phenyl]-2-fluoro-benzonitrile is based on Example 17 (steps 1~4), by using (2-fluoro-4-methyl-phenyl)boronic acid p-tolylboronic acid , And get the title compound.

實施例22　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將實施例1(步驟1)所得到的第三丁基　3-溴-4-氯-苯甲酸酯 1.00g溶解於1,4-二噁烷8.6mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸509mg、Pd(PPh3 )4 119mg、2M Na2 CO3 水溶液 4.3mL，於微波反應裝置中在120℃下攪拌反應液30分鐘。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　4-氯-3-(4-氰基-3-氟-苯基)苯甲酸酯。Example 22 4-[5-[(3-Internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2- (Methoxyethyl)phenyl)phenyl)-2-fluoro-benzonitrile synthesis (step 1) The tertiary butyl 3-bromo-4-chloro-benzene obtained in Example 1 (step 1) 1.00 g of formate was dissolved in 8.6 mL of 1,4-dioxane. At room temperature, 509 mg of (4-cyano-3-fluoro-phenyl)boronic acid, 119 mg of Pd(PPh 3 ) 4 , and 4.3 mL of 2M Na 2 CO 3 aqueous solution were added, and the reaction solution was stirred at 120°C in a microwave reactor 30 minute. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoic acid ester.

(步驟2)將前述步驟1所得到的第三丁基　4-氯-3-(4-氰基-3-氟-苯基)苯甲酸酯 1.00g溶解於1,4-二噁烷15mL中。於室溫添加實施例20(步驟1)所得到的2-[2-氟-4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷　1.69g、Pd(dba)2 138mg、磷酸三鉀 1.28g、1M PCy3 THF溶液 0.30mL。於微波反應裝置中在160℃下攪拌反應液30分鐘。添加氯仿，濾別不溶物，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於TFA 2mL中，並蒸餾去除溶劑。添加乙酸乙酯，並以水、飽和食鹽水依序洗淨。以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑，而得到3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸。(Step 2) Dissolve 1.00 g of the tertiary butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoate obtained in the aforementioned step 1 in 1,4-dioxane 15 mL in. Add 2-[2-fluoro-4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1, obtained in Example 20 (Step 1) at room temperature 3,2-Dioxolane 1.69 g, Pd(dba) 2 138 mg, tripotassium phosphate 1.28 g, 1M PCy 3 THF solution 0.30 mL. The reaction solution was stirred at 160°C for 30 minutes in a microwave reaction device. Add chloroform, filter out the insoluble matter, and distill to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in TFA 2mL, and the solvent was distilled off. Add ethyl acetate, and wash with water and saturated saline in this order. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)benzene基]benzoic acid.

(步驟3)將前述步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸 10mg、第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 5.8mg、HATU 19mg溶解於THF 0.5mL中。於室溫添加TEA 0.007mL，於50℃徹夜攪拌。減壓濃縮反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 3) The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid obtained in the aforementioned step 2 10 mg, 5.8 mg of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate and 19 mg of HATU were dissolved in 0.5 mL of THF. 0.007 mL of TEA was added at room temperature, and stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-内)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl] Carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 10.9mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(2-fluoro- 4-(2-Methoxyethyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 10.9mg was dissolved in 0.3mL of TFA, After confirming the progress of the reaction by LCMS, it was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例23　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-吲哚-5-基)苯基]-2-氟-苯甲腈之合成(步驟1)將實施例18(步驟1)所得到的第三丁基　N-[(3-外)-8-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 270mg溶解於1,4-二噁烷2.8mL中。於室溫添加Pd(OAc)2 2.5mg、KOAc 164mg、雙(品納可基)二硼烷283mg、Silica-SMAP 4.6mg，於150℃徹夜攪拌。以矽藻土過濾，減壓濃縮濾液。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 23 4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- Synthesis of indol-5-yl)phenyl]-2-fluoro-benzonitrile (Step 1) The tertiary butyl N-[(3-外)-8- obtained in Example 18 (Step 1) [4-Chloro-3-(4-cyano-3-fluoro-phenyl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 270mg dissolved in 1,4-dioxane in 2.8 mL. Pd(OAc) 2 2.5 mg, KOAc 164 mg, bis(pinnacyl) diborane 283 mg, and Silica-SMAP 4.6 mg were added at room temperature, and the mixture was stirred at 150°C overnight. It was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-外)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-8-azabicyclo [3.2.1] Octan-3-yl] carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 10mg、5-溴-6-氟-1-甲基-吲哚　4.8mg、PdCl2 (dppf) 0.71mg懸浮於1,4-二噁烷0.5mL中。於室溫添加磷酸三鉀 11mg，於125℃攪拌45分鐘。過濾反應液後，蒸餾去除溶劑，而得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-吲哚-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]amine 10 mg of formate, 4.8 mg of 5-bromo-6-fluoro-1-methyl-indole, and 0.71 mg of PdCl 2 (dppf) were suspended in 0.5 mL of 1,4-dioxane. 11 mg of tripotassium phosphate was added at room temperature, and stirred at 125°C for 45 minutes. After filtering the reaction solution, the solvent was distilled off to obtain tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro- 1-Methyl-indol-5-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-吲哚-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 8mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro- 8-mg of 1-methyl-indol-5-yl)benzyl]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.3mL of TFA and confirmed by LCMS After the reaction progresses, it is concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例24　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-吲唑-5-基)苯基]-2-氟-苯甲腈之合成(步驟1)將實施例23(步驟1)所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 10mg溶解於1,4-二噁烷0.5mL中。於室溫下添加5-溴-6-氟-1-甲基-吲唑　4.8mg、PdCl2 (dppf)　0.71mg、磷酸三鉀 11mg，於微波反應裝置中在125℃攪拌45分鐘。過濾反應液之後蒸餾去除溶劑，而得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-吲唑-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 24 4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- Synthesis of indazol-5-yl)phenyl]-2-fluoro-benzonitrile (Step 1) The tertiary butyl N-[(3-外)-8- obtained in Example 23 (Step 1) [3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 10 mg of benzoyl]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.5 mL of 1,4-dioxane. 4.8 mg of 5-bromo-6-fluoro-1-methyl-indazole, 0.71 mg of PdCl 2 (dppf), and 11 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125° C. for 45 minutes in a microwave reactor. After filtering the reaction liquid, the solvent was distilled off to obtain the tertiary butyl N-[(3-外)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1) -Methyl-indazol-5-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟2)　將前述步驟1所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-吲唑-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) ``The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro- 15 mg of 1-methyl-indazol-5-yl)benzyl]-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 0.3mL of TFA and confirmed by LCMS After the reaction progresses, it is concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例25　4-[5-[(3S)-3-胺基-3-甲基-吡咯啶-1-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將實施例22(步驟2)所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸 10mg、第三丁基　N-[(3S)-3-甲基吡咯啶-3-基]胺甲酸酯 5.1mg溶解於THF 0.5mL中。於室溫添加TEA 0.011mL、HATU 19mg，於50℃攪拌一晩。減壓濃縮反應液，並蒸餾去除溶劑。而得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-3-甲基-吡咯啶-3-基]胺甲酸酯。Example 25 "4-[5-[(3S)-3-amino-3-methyl-pyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)benzene Synthesis of phenyl]phenyl)-2-fluoro-benzonitrile (Step 1) The 3-(4-cyano-3-fluoro-phenyl)-4-[2 -Fluoro-4-(2-methoxyethyl)phenyl]benzoic acid 10mg, tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate 5.1mg dissolved In 0.5mL of THF. TEA 0.011 mL and HATU 19 mg were added at room temperature, and stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. And the third butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl) Phenyl]benzyl]-3-methyl-pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-3-甲基-吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4- (2-Methoxyethyl)phenyl]benzyl)-3-methyl-pyrrolidin-3-yl]carbamate 15mg was dissolved in 0.3mL of TFA, after confirming the progress of the reaction by LCMS Concentrate under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例26　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將實施例22(步驟2)所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸 10mg、第三丁基　N-[(3-外)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 5.8mg溶解於THF 0.5mL中。於室溫添加TEA 0.011mL、HATU 19mg，於50℃攪拌一晩。減壓濃縮反應液，並蒸餾去除溶劑。得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 26 "4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2- Synthesis of methoxyethyl)phenyl)phenyl)-2-fluoro-benzonitrile (Step 1) The 3-(4-cyano-3-fluoro-benzene obtained in Example 22 (Step 2) Yl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid 10mg, tert-butyl N-[(3-exo)-8-azabicyclo[3.2.1 5.8 mg of ]octan-3-yl] carbamate was dissolved in 0.5 mL of THF. TEA 0.011 mL and HATU 19 mg were added at room temperature, and stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. Obtain the tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl) ) Phenyl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro- obtained in step 1 above 4-(2-Methoxyethyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 15mg was dissolved in 0.3mL of TFA to After confirming the progress of the reaction by LCMS, concentration under reduced pressure was performed. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例27　4-[5-(3,8-二氮雜雙環[3.2.1]辛烷-8-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　3,8-二氮雜雙環[3.2.1]辛烷-3-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 27 "4-[5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl ]Phenyl]-2-fluoro-benzonitrile was synthesized in accordance with Example 22 (steps 1 to 4) by using tert-butyl 3,8-diazabicyclo[3.2.1]octane- Instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate with 3-carboxylic acid, the title compound was obtained.

實施例28　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將甲基　2-(4-溴-3-氟-苯基)乙酸酯 500 mg溶解於THF 2.2mL中。於-30℃滴下添加3M MeMgBr 醚溶液 5.40mL，於室溫徹夜攪拌。將反應液注入氯化銨水溶液中，添加乙酸乙酯，並以水、飽和食鹽水依序洗淨。以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：乙酸乙酯/己烷＝10%→50%)純化殘渣，藉此得到1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇。Example 28 "4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2- Synthesis of hydroxy-2-methyl-propyl)phenyl)phenyl)-2-fluoro-benzonitrile (Step 1) Methyl 2-(4-bromo-3-fluoro-phenyl)acetate 500 mg was dissolved in 2.2 mL of THF. 5.40 mL of 3M MeMgBr ether solution was added dropwise at -30°C, and stirred overnight at room temperature. The reaction solution was poured into an aqueous ammonium chloride solution, ethyl acetate was added, and washed with water and saturated brine in this order. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane=10%→50%) to obtain 1-(4-bromo-3-fluoro-phenyl)-2-methyl- Propane-2-ol.

(步驟2)將實施例23(步驟1)所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 68mg、前述步驟1所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇 107mg、Pd(PPh3 )4 6.42mg懸浮於1,4-二噁烷0.93mL中。於室溫添加2M Na2 CO3 水溶液 0.46mL，於125℃攪拌45分鐘。過濾反應液後，蒸餾去除溶劑，而得到第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octane-3 -Yl]carbamate 68mg, 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2-ol 107mg, Pd(PPh 3 ) 4 6.42mg obtained in step 1 above Suspended in 0.93 mL of 1,4-dioxane. 0.46 mL of 2M Na 2 CO 3 aqueous solution was added at room temperature, and stirred at 125°C for 45 minutes. After filtering the reaction liquid, the solvent was distilled off to obtain tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro- 4-(2-Hydroxy-2-methyl-propyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 90mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro- obtained in step 2 above 4-(2-Hydroxy-2-methyl-propyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 90mg dissolved in TFA 0.3 In mL, the progress of the reaction was confirmed by LCMS and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例29　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(羥基甲基)苯基]苯基]苯甲腈之合成(步驟1)將[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲醇 500mg、DMAP 26mg溶解於THF 7.1mL中，添加TEA 0.74mL。於室溫添加乙醯氯 0.23mL，攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲基　乙酸酯。Example 29 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(hydroxymethyl)phenyl]phenyl]benzonitrile (Step 1) Dissolve 500 mg of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol and 26 mg of DMAP in 7.1 mL of THF, Add 0.74 mL of TEA. Add 0.23 mL of acetyl chloride at room temperature, and stir for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain [4-(4,4,5,5-tetramethyl-1,3,2-dioxane) Pentaboran-2-yl)phenyl]methyl acetate.

(步驟2)將實施例9(步驟2)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 100mg、前述步驟1所得到的[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲基　乙酸酯 130mg溶解於1,4-二噁烷1.2mL中。於室溫下添加Pd(dba)2 6.8mg、磷酸三鉀 100mg、1M PCy3 THF溶液 0.02mL。在微波反應裝置中於160℃攪拌1小時。以NH矽膠過濾反應液，蒸餾去除濾液之溶劑。以矽膠管柱層析法(移動相：乙酸乙酯/己烷＝30%→100%)純化殘渣，藉此得到[4-[4-[(3S)-3-(第三丁氧基羰基胺基)吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]甲基　乙酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzyl]pyrrolidine obtained in Example 9 (Step 2) -3-yl]carbamate 100mg, [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl obtained in step 1 above) ) 130 mg of phenyl]methyl acetate was dissolved in 1.2 mL of 1,4-dioxane. Pd(dba) 2 6.8 mg, tripotassium phosphate 100 mg, and 1M PCy 3 THF solution 0.02 mL were added at room temperature. Stir at 160°C for 1 hour in a microwave reaction device. The reaction solution was filtered with NH silica gel, and the solvent of the filtrate was removed by distillation. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane=30%→100%) to obtain [4-[4-[(3S)-3-(tertiary butoxycarbonyl) Amino)pyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]methyl acetate.

(步驟3)將前述步驟2所得到的[4-[4-[(3S)-3-(第三丁氧基羰基胺基)吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]甲基　乙酸酯 100mg溶解於MeOH 2mL中。於室溫添加K2 CO3 65mg，於室溫攪拌30分鐘。添加氯仿，依序以飽和氯化銨水溶液、飽和食鹽水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：乙酸乙酯/己烷＝40%→100%)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(羥基甲基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 3) The [4-[4-[(3S)-3-(third butoxycarbonylamino)pyrrolidine-1-carbonyl]-2-(4-cyanobenzene 100 mg of phenyl]phenyl]methyl acetate was dissolved in 2 mL of MeOH. 65 mg of K 2 CO 3 was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Chloroform was added, washed with saturated ammonium chloride aqueous solution and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane=40%→100%) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanide Phenyl)-4-[4-(hydroxymethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(羥基甲基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(hydroxymethyl)phenyl]benzene obtained in the aforementioned step 3 15 mg of methanoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例30　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-甲氧基乙基)苯基]苯基]苯甲腈之合成(步驟1)將1-溴-4-(2-甲氧基乙基)苯 450mg溶解於1,4-二噁烷5.2mL中。添加雙(品納可基)二硼烷797mg、KOAc 411mg、PdCl2 (dppf)　77mg，於90℃徹夜攪拌。添加乙酸乙酯，進行矽藻土過濾後，以水、飽和食鹽水依序洗淨濾液，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：乙酸乙酯/己烷＝2%→20%)純化殘渣，藉此得到2-[4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷。Example 30 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methoxyethyl)phenyl]phenyl]benzonitrile (Step 1) Dissolve 450 mg of 1-bromo-4-(2-methoxyethyl)benzene in 5.2 mL of 1,4-dioxane. Add 797 mg of bis(pinnacyl) diborane, 411 mg of KOAc, and 77 mg of PdCl 2 (dppf), and stir at 90°C overnight. After adding ethyl acetate and performing Celite filtration, the filtrate was washed sequentially with water and saturated brine, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane=2%→20%) to obtain 2-[4-(2-methoxyethyl)phenyl]-4, 4,5,5-Tetramethyl-1,3,2-dioxolane.

(步驟2)　將實施例9(步驟2)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 300mg、前述步驟1所得到的2-[4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷　369mg溶解於1,4-二噁烷2mL中。於室溫下添加Pd(dba)2 32mg、磷酸三鉀 300mg、1M PCy3 THF溶液 0.07mL，於微波反應裝置中在160℃攪拌45分鐘。以矽藻土過濾反應液，蒸餾去除濾液之溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(2-甲氧基乙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzyl]pyrrolidine obtained in Example 9 (Step 2) -3-yl]carbamate 300 mg, 2-[4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3 obtained in step 1 above 369mg of ,2-dioxolane was dissolved in 2mL of 1,4-dioxane. At room temperature, 32 mg of Pd(dba) 2 , 300 mg of tripotassium phosphate, and 0.07 mL of 1M PCy 3 THF solution were added, and the mixture was stirred at 160° C. for 45 minutes in a microwave reactor. The reaction solution was filtered with celite, and the solvent of the filtrate was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2) -Methoxyethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(2-甲氧基乙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-methoxyethyl) obtained in the aforementioned step 2 15 mg of phenyl]benzyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例31　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基乙基)苯基]苯基]苯甲腈之合成　以實施例29(步驟1~4)為準，藉由使用2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]乙醇來代替[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲醇，而得到標題化合物。Example 31 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxyethyl)phenyl]phenyl]benzonitrile for implementation Example 29 (Steps 1~4) shall prevail, by using 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl]ethanol was substituted for [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol to obtain the title compound.

實施例32　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(3-羥基丙基)苯基]苯基]苯甲腈之合成　以實施例29(步驟1~4)為準，藉由使用3-[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]丙烷-1-醇來代替[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲醇，而得到標題化合物。Example 32 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxypropyl)phenyl]phenyl]benzonitrile for implementation Example 29 (Steps 1 to 4) shall prevail, by using 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl]propane-1-ol instead of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol, and The title compound is obtained.

實施例33　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-[1-(羥基甲基)環丙基]苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用(1-(4-溴苯基)環丙基)甲醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 33 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]phenyl]benzyl The synthesis of nitrile is based on Example 9 (steps 1 to 5), by using (1-(4-bromophenyl)cyclopropyl)methanol instead of 1-bromo-2-chloro-4-methyl-benzene , And get the title compound.

實施例34　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基-2-甲基-丙基)苯基]苯基]苯甲腈之合成　以實施例9(步驟1~5)為準，藉由使用1-(4-溴苯基)-2-甲基丙烷-2-醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 34 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]benzene The synthesis of formonitrile is based on Example 9 (steps 1 to 5), by using 1-(4-bromophenyl)-2-methylpropane-2-ol instead of 1-bromo-2-chloro-4 -Methyl-benzene to obtain the title compound.

實施例35　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基丙氧基)苯基]苯基]苯甲腈之合成(步驟1)以實施例12(步驟1)為準，藉由使用(4-苯甲基氧基苯基)硼酸來代替4-甲基-2-硝基苯基硼酸　品納可　酯，藉此得到第三丁基　N-[(3S)-1-[4-(4-苯甲基氧基苯基)-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 35 　 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxypropoxy)phenyl]phenyl]benzonitrile ( Step 1) According to Example 12 (Step 1), by using (4-benzyloxyphenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacyl ester, Obtain the tertiary butyl N-[(3S)-1-[4-(4-benzyloxyphenyl)-3-(4-cyanophenyl)benzyl]pyrrolidin-3-yl ] Carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[4-(4-苯甲基氧基苯基)-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 800mg、氫氧化鈀碳　160mg懸浮於EtOH 20mL中。進行氫取代，於室溫攪拌6小時。將反應液進行矽藻土過濾，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4-羥基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[4-(4-benzyloxyphenyl)-3-(4-cyanophenyl)benzene obtained in step 1 above 800 mg of methanoyl]pyrrolidin-3-yl]carbamate and 160 mg of palladium hydroxide on carbon were suspended in 20 mL of EtOH. Carry out hydrogen substitution and stir at room temperature for 6 hours. The reaction solution was filtered through Celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4 -(4-Hydroxyphenyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4-羥基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於DMF 0.5mL中。於室溫添加K2 CO3 6.4mg、2-甲基環氧乙烷 5.4mg，於120℃攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(2-羥基丙氧基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 3) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-hydroxyphenyl)benzyl] obtained in step 2 above 15 mg of pyrrolidin-3-yl] carbamate was dissolved in 0.5 mL of DMF. 6.4 mg of K 2 CO 3 and 5.4 mg of 2-methyloxirane were added at room temperature, and the mixture was stirred at 120°C for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4 -[4-(2-Hydroxypropoxy)phenyl]benzyl]pyrrolidin-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-[4-(2-羥基丙氧基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-hydroxypropoxy)benzene obtained in the aforementioned step 3 15 mg of benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例36　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2-氟-4-甲基-苯基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用(2-氟-4-甲基-苯基)硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 36 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-fluoro-4-methyl-phenyl)phenyl]-2-fluoro-benzyl The synthesis of nitrile was based on Example 16 (steps 1 to 3), and the title compound was obtained by using (2-fluoro-4-methyl-phenyl)boronic acid instead of p-tolylboronic acid.

實施例37　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將實施例16(步驟1)所得到的第三丁基　N-[(3S)-1-[4-氯-3-(4-氰基-3-氟-苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 4g溶解於1,4-二噁烷45mL中。於室溫添加Pd(OAc)2 0.40g、KOAc 2.7g、雙(品納可基)二硼烷 4.6g、Silica-SMAP 0.72g，於150℃攪拌18小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 37 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl] Synthesis of phenyl]-2-fluoro-benzonitrile (step 1) The tertiary butyl N-[(3S)-1-[4-chloro-3-(4 -Cyano-3-fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate 4g was dissolved in 45mL of 1,4-dioxane. Pd(OAc) 2 0.40 g, KOAc 2.7 g, bis(pinnacyl) diborane 4.6 g, and Silica-SMAP 0.72 g were added at room temperature, and the mixture was stirred at 150°C for 18 hours. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro- (Phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-yl)amine Formate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 30mg、實施例28(步驟1)所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇 28mg溶解於1,4-二噁烷0.8mL中。於室溫添加Pd(PPh3 )4 3.2mg、2M Na2 CO3 水溶液 0.4mL，於微波反應裝置中在120℃攪拌30分鐘。過濾反應液，並蒸餾去除溶劑。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate 30mg, as described in Example 28 (Step 1) 28 mg of the obtained 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2-ol was dissolved in 0.8 mL of 1,4-dioxane. At room temperature, 3.2 mg of Pd(PPh 3 ) 4 and 0.4 mL of a 2M Na 2 CO 3 aqueous solution were added, and the mixture was stirred at 120° C. for 30 minutes in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-[2-Fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzyl]pyrrolidin-3-yl]carbamate.

(步驟3)將前述步驟2所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 20mg溶解於MeOH 1mL中。於室溫添加12M HCl水溶液 1mL，於室溫攪拌30分鐘。於反應液中添加水 1mL、2M 氫氧化鈉水溶液 6mL而進行中和。添加氯仿，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到標題化合物。(Step 3) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4- 20 mg of (2-hydroxy-2-methyl-propyl)phenyl]benzyl]pyrrolidin-3-yl]carbamate was dissolved in 1 mL of MeOH. 1 mL of 12M HCl aqueous solution was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, 1 mL of water and 6 mL of a 2M sodium hydroxide aqueous solution were added for neutralization. Chloroform was added, washed with water and saturated saline in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound.

實施例38　2-氟-4-[2-[2-氟-4-(2-甲氧基乙基)苯基]-5-(9-氧雜-2,6-二氮雜螺[3.5]壬烷-2-羰基)苯基]苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　9-氧雜-2,6-二氮雜螺[3.5]壬烷-6-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 38 "2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-(9-oxa-2,6-diazaspiro[3.5 ]Nonane-2-carbonyl)phenyl]benzonitrile was synthesized in accordance with Example 22 (steps 1 to 4) by using tertiary butyl 9-oxa-2,6-diazaspiro[ 3.5] Nonane-6-carboxylic acid replaces the tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound .

實施例39　4-[5-(2,3,3a,4,6,6a-六氫-1H-吡咯并[3,4-c]吡咯-5-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　2,3,3a,4,6,6a-六氫-1H-吡咯并[3,4-c]吡咯-5-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 39 "4-[5-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl)-2-[2-fluoro-4 -(2-Methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile was synthesized according to Example 22 (steps 1 to 4), by using tertiary butyl 2,3, 3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid instead of tertiary butyl N-[(3-internal)-8-azabicyclo[3.2 .1]octan-3-yl]carbamate to obtain the title compound.

實施例40　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈以實施例37(步驟1~3)為準，藉由使用1-(4-溴苯基)-2-甲基丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 40 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]- 2-Fluoro-benzonitrile is based on Example 37 (Steps 1~3), by using 1-(4-bromophenyl)-2-methylpropane-2-ol instead of 1-(4-bromo -3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例41　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)　將實施例22(步驟1)所得到的第三丁基　4-氯-3-(4-氰基-3-氟-苯基)苯甲酸酯 300mg溶解於1,4-二噁烷5mL中。於室溫添加Pd(OAc)2 40mg、KOAc 300mg、雙(品納可基)二硼烷 500mg、Silica-SMAP 50mg，於100℃攪拌26小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯。Example 41 4-[5-[(3-Internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2- Synthesis of hydroxy-2-methyl-propyl)phenyl)phenyl)-2-fluoro-benzonitrile (Step 1) The tertiary butyl 4-chloro-3 obtained in Example 22 (Step 1) 300 mg of -(4-cyano-3-fluoro-phenyl)benzoate was dissolved in 5 mL of 1,4-dioxane. 40 mg of Pd(OAc) 2 , 300 mg of KOAc, 500 mg of bis(pinacyl) diborane, and 50 mg of Silica-SMAP were added at room temperature, and the mixture was stirred at 100°C for 26 hours. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4) ,5,5-Tetramethyl-1,3,2-dioxole-2-yl)benzoate.

(步驟2)將前述步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 100mg溶解於DCM 1.2mL中。於室溫添加TFA 1.00mL，於室溫攪拌30分鐘。減壓濃縮反應液，並蒸餾去除溶劑。添加氯仿，以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸。(Step 2) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3, 100 mg of 2-dioxole-2-yl)benzoate was dissolved in 1.2 mL of DCM. 1.00 mL of TFA was added at room temperature, and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. Chloroform was added, washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

(步驟3)　將前述步驟2所得到的3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸 500mg、第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 308mg溶解於THF 4.5mL中。於室溫添加TEA 0.57mL、HATU 1g，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 3) ``The 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxide obtained in the aforementioned step 2 Dissolved in 500mg of cyclopentaborane-2-yl)benzoic acid and 308mg of tert-butyl N-[(3-internal)-8-azabicyclo[3.2.1]octane-3-yl]carbamate In 4.5mL of THF. 0.57 mL of TEA and 1 g of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-内)-8-[3-(4 -Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) -8-Azabicyclo[3.2.1]octan-3-yl]carbamate.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 30mg、實施例28(步驟1)所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇 19mg溶解於1,4-二噁烷0.5mL中。於室溫下添加Pd(PPh3 )4 18mg、2M Na2 CO3 水溶液 0.3mL，於微波反應裝置中在120℃攪拌30分鐘。取反應液上清液並進行NH矽膠過濾，蒸餾去除溶劑，藉此得到第三丁基-N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 4) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]amine 30 mg of formate and 19 mg of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2-ol obtained in Example 28 (Step 1) were dissolved in 1,4-dioxane 0.5mL in. At room temperature, 18 mg of Pd(PPh 3 ) 4 and 0.3 mL of a 2M Na 2 CO 3 aqueous solution were added, and the mixture was stirred at 120° C. for 30 minutes in a microwave reactor. Take the supernatant of the reaction solution and filter with NH silica gel, and distill off the solvent to obtain tertiary butyl-N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl) )-4-[2-Fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octane-3-yl] Carbamate.

(步驟5)將前述步驟4所得到的第三丁基-N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 15mg溶解於MeOH 0.5mL中。於室溫添加12M HCl水溶液 0.5mL，並於室溫攪拌30分鐘。添加水、2M 氫氧化鈉水溶液 3mL，並以氯仿進行分液萃取。以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The tertiary butyl-N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro -4-(2-Hydroxy-2-methyl-propyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 15mg dissolved in MeOH 0.5mL in. 0.5 mL of 12M HCl aqueous solution was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Add water and 3 mL of 2M sodium hydroxide aqueous solution, and perform separation and extraction with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例42　4-[5-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]-2-(對甲苯基)苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用(S)、第三丁基　甲基(吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 42 　 The synthesis of 4-[5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile according to Example 1 (Step 1~5) shall prevail, by using (S), tertiary butyl methyl (pyrrolidin-3-yl) carbamate instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl] Carbamate to obtain the title compound.

實施例43　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-苯甲基氧基苯基)苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-(苯甲基氧基)-4-溴苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 43 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-benzyloxyphenyl)phenyl]benzonitrile Take Example 9 (Steps 1 to 5) are the standard, and the title compound is obtained by using 1-(benzyloxy)-4-bromobenzene instead of 1-bromo-2-chloro-4-methyl-benzene.

實施例44　1-[4-[4-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]-N-苯基-環丙烷甲醯胺之合成以實施例9(步驟1~5)為準，藉由使用1-(4-溴苯基)-N-苯基環丙烷甲醯胺來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 44 "1-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]-N-phenyl- The synthesis of cyclopropane carboxamide is based on Example 9 (steps 1 to 5), by using 1-(4-bromophenyl)-N-phenylcyclopropane carboxamide instead of 1-bromo-2- Chloro-4-methyl-benzene to obtain the title compound.

實施例45　2-[4-[4-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]乙基　乙酸酯之合成(步驟1)以實施例29(步驟1)為準，藉由使用2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基)乙醇來代替[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]甲醇，藉此得到4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯乙基　乙酸酯。Example 45 　 2-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]ethyl acetate The synthesis (step 1) was based on Example 29 (step 1), by using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane -2-yl)phenyl)ethanol instead of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol, Thus, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl acetate was obtained.

(步驟2)以實施例12(步驟1~2)為準，藉由使用前述步驟1所得到的4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯乙基　乙酸酯來代替4-甲基-2-硝基苯基硼酸,品納可　酯，而得到標題化合物。(Step 2) According to Example 12 (Steps 1~2), by using the 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)phenethyl acetate replaces 4-methyl-2-nitrophenylboronic acid, pinnacle ester, to obtain the title compound.

實施例46　4-[2-[4-(2-羥基乙基)苯基]-5-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]苯基]苯甲腈之合成(步驟1)　以實施例1(步驟1~5)為準，藉由使用實施例45(步驟1)所得到的4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯乙基　乙酸酯來代替對甲苯基硼酸，且藉由使用(S)、第三丁基　甲基(吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到2-[4-[2-(4-氰基苯基)-4-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]苯基]苯基]乙基　乙酸酯。Example 46 　 4-[2-[4-(2-hydroxyethyl)phenyl]-5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]phenyl]benzonitrile The synthesis (step 1)" is based on Example 1 (steps 1 to 5), by using the 4-(4,4,5,5-tetramethyl-1,3) obtained in Example 45 (step 1) ,2-Dioxolaborin-2-yl)phenethyl acetate instead of p-tolylboronic acid, and by using (S), tertiary butylmethyl(pyrrolidin-3-yl)carbamate Instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain 2-[4-[2-(4-cyanophenyl)-4-[( 3S)-3-(methylamino)pyrrolidine-1-carbonyl]phenyl]phenyl]ethyl acetate.

(步驟2)以實施例29(步驟3)為準，藉由使用前述步驟1所得到的2-[4-[2-(4-氰基苯基)-4-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]苯基]苯基]乙基　乙酸酯來代替[4-[4-[(3S)-3-(第三丁氧基羰基胺基)吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]甲基　乙酸酯，而得到標題化合物。(Step 2) Based on Example 29 (Step 3), by using the 2-[4-[2-(4-cyanophenyl)-4-[(3S)-3- (Methylamino)pyrrolidine-1-carbonyl]phenyl)phenyl]ethyl acetate instead of [4-[4-[(3S)-3-(tertiary butoxycarbonylamino)pyrrole Pyridin-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]methyl acetate to obtain the title compound.

實施例47　4-[2-[4-(2-甲氧基乙基)苯基]-5-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]苯基]苯甲腈之合成(步驟1)以實施例1(步驟1~5)為準，藉由使用(4-(2-甲氧基乙基)苯基)硼酸來代替對甲苯基硼酸，且藉由使用(S)、第三丁基　甲基(吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 47 "4-[2-[4-(2-Methoxyethyl)phenyl]-5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]phenyl]benzene The synthesis of formonitrile (step 1) is based on Example 1 (steps 1 to 5), by using (4-(2-methoxyethyl)phenyl)boronic acid instead of p-tolylboronic acid, and by Use (S), tertiary butyl methyl (pyrrolidin-3-yl) carbamate instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl] carbamate to obtain the title compound .

實施例48　4-[5-[(3S)-3-(二甲基胺基)吡咯啶-1-羰基]-2-[4-[1-(羥基甲基)環丙基]苯基]苯基]苯甲腈之合成以實施例1(步驟1~4)為準，藉由使用[4-[1-(羥基甲基)環丙基]苯基]硼酸來代替對甲苯基硼酸，藉由使用(S)-N,N-二甲基吡咯啶-3-胺來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 48 "4-[5-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl] The synthesis of phenyl]benzonitrile is based on Example 1 (Steps 1~4), by using [4-[1-(hydroxymethyl)cyclopropyl]phenyl]boronic acid instead of p-tolylboronic acid, The title compound was obtained by using (S)-N,N-dimethylpyrrolidin-3-amine instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate.

實施例49　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(3-氟-4-甲基-苯基)苯基]苯甲腈之合成以實施例12(步驟1~2)為準，藉由使用(3-氟-4-甲基-苯基)硼酸來代替4-甲基-2-硝基苯基硼酸　品納可　酯，而得到標題化合物。Example 49 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-fluoro-4-methyl-phenyl)phenyl]benzonitrile for implementation Example 12 (Steps 1~2) shall prevail, by using (3-fluoro-4-methyl-phenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacyl ester to obtain the title Compound.

實施例50　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-氯苯基)苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-溴-4-氯-苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 50 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-chlorophenyl)phenyl]benzonitrile was used in Example 9 (Step 1~ 5) As the standard, the title compound is obtained by using 1-bromo-4-chloro-benzene instead of 1-bromo-2-chloro-4-methyl-benzene.

實施例51　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-溴苯基)苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1,4-二溴苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 51 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-bromophenyl)phenyl]benzonitrile was used in Example 9 (Step 1~ 5) As the standard, the title compound is obtained by using 1,4-dibromobenzene instead of 1-bromo-2-chloro-4-methyl-benzene.

實施例52　5'-((1S,4S)-2,5-二氮雜雙環[2.2.1]庚烷-2-羰基)-4''-甲基-[1,1':2',1'-三聯苯]-4-甲腈之合成以實施例1(步驟1~5)為準，藉由使用第三丁基　(1S,4S)-2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 52 ``5'-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-4''-methyl-[1,1':2', The synthesis of 1'-terphenyl]-4-carbonitrile is based on Example 1 (steps 1 to 5), by using tertiary butyl (1S,4S)-2,5-diazabicyclo[2.2. 1] Heptane-2-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例53　4-[2-[4-(2-胺基乙基)苯基]-5-[(3S)-3-胺基吡咯啶-1-羰基]苯基]苯甲腈之合成(步驟1)將實施例9(步驟3)所得到的第三丁基　N-[(3S)-1-[3-(4-氰基苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 50mg溶解於1,4-二噁烷0.48mL中。於室溫添加2-(4-溴苯基)乙烷胺 29mg、Pd(PPh3 )4 3.4mg、2M Na2 CO3 水溶液 0.24mL，於微波反應裝置中在120℃攪拌30分鐘。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[4-[4-(2-胺基乙基)苯基]-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 53 Synthesis of 4-[2-[4-(2-aminoethyl)phenyl]-5-[(3S)-3-aminopyrrolidine-1-carbonyl]phenyl]benzonitrile ( Step 1) The tertiary butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate 50mg dissolved in 0.48mL of 1,4-dioxane in. At room temperature, 29 mg of 2-(4-bromophenyl) ethaneamine, 3.4 mg of Pd(PPh 3 ) 4 and 0.24 mL of 2M Na 2 CO 3 aqueous solution were added, and the mixture was stirred at 120° C. for 30 minutes in a microwave reactor. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[4-[4-(2-aminoethyl) )Phenyl]-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)　將前述步驟1所得到的第三丁基　N-[(3S)-1-[4-[4-(2-胺基乙基)苯基]-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) ``The tertiary butyl N-[(3S)-1-[4-[4-(2-aminoethyl)phenyl]-3-(4-cyanobenzene 15 mg of benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例54　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-碘苯基)苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1,4-二碘苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 54 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-iodophenyl)phenyl]benzonitrile was used in Example 9 (Step 1~ 5) As the standard, the title compound is obtained by using 1,4-diiodobenzene instead of 1-bromo-2-chloro-4-methyl-benzene.

實施例55　N-[2-[4-[4-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-氰基苯基)苯基]苯基]乙基]乙醯胺之合成將實施例53(步驟1)所得到的第三丁基　N-[(3S)-1-[4-[4-(2-胺基乙基)苯基]-3-(4-氰基苯基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於THF中。於室溫添加TEA 0.02mL，接著添加乙醯氯 4.6mg，並於室溫攪拌1小時。對殘渣添加TFA，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 55 "N-[2-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]ethyl] Synthesis of Acetamide The tertiary butyl N-[(3S)-1-[4-[4-(2-aminoethyl)phenyl]-3-( 15 mg of 4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate was dissolved in THF. 0.02 mL of TEA was added at room temperature, followed by 4.6 mg of acetyl chloride, and the mixture was stirred at room temperature for 1 hour. TFA was added to the residue, and after the progress of the reaction was confirmed by LCMS, it was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例56　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-丙基苯基)苯基]苯甲腈之合成以實施例12(步驟1~2)為準，藉由使用(4-丙基苯基)硼酸來代替4-甲基-2-硝基苯基硼酸品納可　酯，而得到標題化合物。Example 56 　 Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-propylphenyl)phenyl]benzonitrile according to Example 12 (Step 1 ~2) shall prevail, by using (4-propylphenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacyl ester to obtain the title compound.

實施例57　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2-萘基)苯基]苯甲腈之合成以實施例12(步驟1~2)為準，藉由使用2-萘基硼酸來代替4-甲基-2-硝基苯基硼酸品納可　酯，而得到標題化合物。Example 57 The synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-naphthyl)phenyl]benzonitrile was used in Example 12 (Steps 1-2 ) Shall prevail, and the title compound is obtained by using 2-naphthylboronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacyl ester.

實施例58　4-[2-[4-[1-(羥基甲基)環丙基]苯基]-5-[(3S)-3-(甲基胺基)吡咯啶-1-羰基]苯基]苯甲腈之合成以實施例1(步驟1~5)為準，藉由使用[4-[1-(羥基甲基)環丙基]苯基]硼酸來代替對甲苯基硼酸，且藉由使用(S)、第三丁基　甲基(吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 58 "4-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]benzene The synthesis of benzonitrile is based on Example 1 (steps 1 to 5), by using [4-[1-(hydroxymethyl)cyclopropyl]phenyl]boronic acid instead of p-tolylboronic acid, and By using (S), tertiary butyl methyl (pyrrolidin-3-yl) carbamate instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl] carbamate, it is obtained Title compound.

實施例59　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-[(1-羥基環丙基)甲基]苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-[(4-溴苯基)甲基]環丙醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 59 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[(1-hydroxycyclopropyl)methyl]phenyl]phenyl]benzyl The synthesis of nitrile is based on Example 9 (steps 1 to 5), by using 1-[(4-bromophenyl)methyl]cyclopropanol instead of 1-bromo-2-chloro-4-methyl- Benzene to obtain the title compound.

實施例60　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-甲基丙-1-烯基)苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-溴-4-(2-甲基丙-1-烯基)苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 60 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methylprop-1-enyl)phenyl]phenyl]benzyl The synthesis of nitrile is based on Example 9 (steps 1 to 5), by using 1-bromo-4-(2-methylprop-1-enyl)benzene instead of 1-bromo-2-chloro-4- Methyl-benzene to obtain the title compound.

實施例61　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(3-羥基-3-甲基-丁基)苯基]苯基]苯甲腈之合成　以實施例9(步驟1~5)為準，藉由使用4-(4-溴苯基)-2-甲基-丁烷-2-醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 61 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxy-3-methyl-butyl)phenyl]phenyl]benzene The synthesis of formonitrile is based on Example 9 (steps 1 to 5), by using 4-(4-bromophenyl)-2-methyl-butane-2-ol instead of 1-bromo-2-chloro -4-methyl-benzene to obtain the title compound.

實施例62　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-[2-(1-羥基環丙基)乙基]苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-[2-(4-溴苯基)乙基]環丙醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 62 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[2-(1-hydroxycyclopropyl)ethyl]phenyl]phenyl] The synthesis of benzonitrile is based on Example 9 (steps 1 to 5), by using 1-[2-(4-bromophenyl)ethyl]cyclopropanol instead of 1-bromo-2-chloro-4 -Methyl-benzene to obtain the title compound.

實施例63　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用2-(4-溴苯基)乙醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 63 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxyethyl)phenyl]phenyl]-2-fluoro-benzyl The synthesis of nitrile is based on Example 37 (Steps 1~3), by using 2-(4-bromophenyl)ethanol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl -Propan-2-ol to obtain the title compound.

實施例64　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用實施例28(步驟1)所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 64 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl] The synthesis of phenyl]benzonitrile was based on Example 9 (Steps 1 to 5), by using the 1-(4-bromo-3-fluoro-phenyl)-2 obtained in Example 28 (Step 1) -Methyl-propan-2-ol instead of 1-bromo-2-chloro-4-methyl-benzene to obtain the title compound.

實施例65　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(3-羥基-3-甲基-丁基)苯基]苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用2-甲基-4-[4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基]丁烷-2-醇來代替對甲苯基硼酸，而得到標題化合物。Example 65 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxy-3-methyl-butyl)phenyl]phenyl]- The synthesis of 2-fluoro-benzonitrile was based on Example 16 (Steps 1~3), by using 2-methyl-4-[4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenyl]butan-2-ol was substituted for p-tolylboronic acid to obtain the title compound.

實施例66　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-[1-(甲氧基甲基)環丙基]苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-溴-4-[1-(甲氧基甲基)環丙基]苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 66" 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(methoxymethyl)cyclopropyl]phenyl]phenyl] The synthesis of benzonitrile was based on Example 9 (steps 1 to 5), and 1-bromo-4-[1-(methoxymethyl)cyclopropyl]benzene was used instead of 1-bromo-2- Chloro-4-methyl-benzene to obtain the title compound.

實施例67　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-[(1-羥基環丙基)甲基]苯基]苯基]苯甲腈之合成　(步驟1)　將甲基-2-(4-溴-3-氟-苯基)乙酸酯 500mg、正鈦酸四異丙基　0.84mL溶解於THF 5mL中。於0℃滴下3M EtMgBr　二乙基醚溶液 1.9mL，於室溫攪拌一晩。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-[(4-溴-3-氟-苯基)甲基]環丙醇。Example 67 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-[(1-hydroxycyclopropyl)methyl]phenyl]benzene Synthesis of benzonitrile (Step 1) "500 mg of methyl-2-(4-bromo-3-fluoro-phenyl) acetate and 0.84 mL of tetraisopropyl n-titanate were dissolved in 5 mL of THF. 1.9 mL of 3M EtMgBr" diethyl ether solution was dropped at 0°C, and stirred at room temperature overnight. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-[(4-bromo-3-fluoro-phenyl)methyl]cyclopropanol.

(步驟2)以實施例9(步驟1~5)為準，藉由使用前述步驟1所得到的1-[(4-溴-3-氟-苯基)甲基]環丙醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。(Step 2) According to Example 9 (Steps 1 to 5), the 1-[(4-bromo-3-fluoro-phenyl)methyl]cyclopropanol obtained in step 1 above was used instead of 1 -Bromo-2-chloro-4-methyl-benzene to obtain the title compound.

實施例68　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-[1-(1-羥基環丙基)環丙基]苯基]苯基]苯甲腈之合成(步驟1)以實施例67(步驟1)為準，藉由使用甲基　1-(4-溴苯基)環丙烷羧酸來代替甲基-2-(4-溴-3-氟-苯基)乙酸酯，藉此得到1-[1-(4-溴苯基)環丙基]環丙醇。Example 68 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(1-hydroxycyclopropyl)cyclopropyl]phenyl]phenyl ] The synthesis of benzonitrile (step 1) was based on Example 67 (step 1), by using methyl 1-(4-bromophenyl)cyclopropane carboxylic acid instead of methyl-2-(4-bromo -3-fluoro-phenyl)acetate, thereby obtaining 1-[1-(4-bromophenyl)cyclopropyl]cyclopropanol.

(步驟2)以實施例9(步驟1~5)為準，藉由使用前述步驟1所得到的1-[1-(4-溴苯基)環丙基]環丙醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。(Step 2) Based on Example 9 (Steps 1 to 5), the 1-[1-(4-bromophenyl)cyclopropyl]cyclopropanol obtained in step 1 above was used instead of 1-bromo -2-chloro-4-methyl-benzene to obtain the title compound.

實施例69　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用實施例30(步驟1)所得到的2-[4-(2-甲氧基乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷來代替對甲苯基硼酸，而得到標題化合物。Example 69 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro- The synthesis of benzonitrile was based on Example 16 (Steps 1 to 3), by using the 2-[4-(2-methoxyethyl)phenyl]-4 obtained in Example 30 (Step 1) ,4,5,5-tetramethyl-1,3,2-dioxolane was substituted for p-tolylboronic acid to obtain the title compound.

實施例70　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基乙基)苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用2-(4-溴-3-氟-苯基)乙醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 70 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxyethyl)phenyl]phenyl]benzonitrile The synthesis is based on Example 9 (steps 1 to 5), by using 2-(4-bromo-3-fluoro-phenyl)ethanol instead of 1-bromo-2-chloro-4-methyl-benzene, The title compound is obtained.

實施例71　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]苯甲腈之合成　以實施例9(步驟1~5)為準，藉由使用1-溴-2-氟-4-(2-甲氧基乙基)苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 71 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]benzene The synthesis of carbonitrile was based on Example 9 (steps 1 to 5), by using 1-bromo-2-fluoro-4-(2-methoxyethyl)benzene instead of 1-bromo-2-chloro- 4-methyl-benzene to obtain the title compound.

實施例72　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-羥基-1,1-二甲基-乙基)苯基]苯基]苯甲腈之合成　以實施例9(步驟1~5)為準，藉由使用2-(4-溴苯基)-2-甲基-丙烷-1-醇來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 72" 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]benzene The synthesis of benzonitrile is based on Example 9 (steps 1 to 5), and 2-(4-bromophenyl)-2-methyl-propane-1-ol is used instead of 1-bromo-2 -Chloro-4-methyl-benzene to obtain the title compound.

實施例73　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[4-(2-氟乙基)苯基]苯基]苯甲腈之合成以實施例9(步驟1~5)為準，藉由使用1-溴-4-(2-氟乙基)苯來代替1-溴-2-氯-4-甲基-苯，而得到標題化合物。Example 73 "Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-fluoroethyl)phenyl]phenyl]benzonitrile for implementation Example 9 (Steps 1 to 5) shall prevail. By using 1-bromo-4-(2-fluoroethyl)benzene instead of 1-bromo-2-chloro-4-methyl-benzene, the title compound is obtained.

實施例74　4-[5-(2,7-二氮雜螺[3.4]辛烷-7-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　2,7-二氮雜螺[3.4]辛烷-2-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 74 "4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile is based on Example 22 (steps 1 to 4), by using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylic acid Instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate, the title compound was obtained.

實施例75　4-[5-(2,8-二氮雜螺[3.5]壬烷-2-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　2,8-二氮雜螺[3.5]壬烷-8-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 75 　 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile is based on Example 22 (steps 1 to 4), by using tert-butyl 2,8-diazaspiro[3.5]nonane-8-carboxylic acid Instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate, the title compound was obtained.

實施例76　4-[5-(2,7-二氮雜螺[3.4]辛烷-7-羰基)-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例41(步驟1~5)為準，藉由使用第三丁基　2,7-二氮雜螺[3.4]辛烷-2-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 76 "4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl) The synthesis of phenyl]phenyl]-2-fluoro-benzonitrile was based on Example 41 (steps 1 to 5), by using tert-butyl 2,7-diazaspiro[3.4]octane- 2-carboxylic acid was substituted for tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例77　4-[5-(2,8-二氮雜螺[3.5]壬烷-2-羰基)-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例41(步驟1~5)為準，藉由使用第三丁基　2,8-二氮雜螺[3.5]壬烷-8-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 77" 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl) The synthesis of phenyl]phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using tert-butyl 2,8-diazaspiro[3.5]nonane- The 8-carboxylic acid replaces the tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例78　4-[5-(3,8-二氮雜螺[4.5]癸烷-8-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈　鹽酸鹽之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　3,8-二氮雜螺[4.5]癸烷-3-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 78 　 4-[5-(3,8-diazaspiro[4.5]decane-8-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile hydrochloride is based on Example 22 (steps 1 to 4), by using tertiary butyl 3,8-diazaspiro[4.5]decane-3 -Carboxylic acid instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例79　4-[5-(2,8-二氮雜螺[3.5]壬烷-8-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　2,8-二氮雜螺[3.5]壬烷-2-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 79 　 4-[5-(2,8-diazaspiro[3.5]nonane-8-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile is based on Example 22 (Steps 1~4), by using tert-butyl 2,8-diazaspiro[3.5]nonane-2-carboxylic acid Instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate, the title compound was obtained.

實施例80　4-[5-(1,4-二吖

Figure 107117996-A0101-12-0012-002
-1-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈　鹽酸鹽之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基-1,4-二吖
Figure 107117996-A0101-12-0012-002
-1-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 80 4-[5-(1,4-Diaza
Figure 107117996-A0101-12-0012-002
-1-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile hydrochloride was synthesized in Example 22 (Step 1 ~4) shall prevail, by using tertiary butyl-1,4-dioxa
Figure 107117996-A0101-12-0012-002
-1-carboxylic acid was substituted for tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例81　4-[5-(3,7-二氮雜螺[3.4]辛烷-7-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基-3,7-二氮雜螺[3.4]辛烷-3-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 81" 4-[5-(3,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of phenyl]-2-fluoro-benzonitrile is based on Example 22 (Steps 1~4), by using tert-butyl-3,7-diazaspiro[3.4]octane-3-carboxy Acid replaces the tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例82　4-[5-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚烷-2-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　(1S,4S)-2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 82 "4-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]-2-[2-fluoro-4-(2-methoxy The synthesis of phenylethyl)phenyl]phenyl)-2-fluoro-benzonitrile is based on Example 22 (steps 1~4), by using tertiary butyl(1S,4S)-2,5- Diazabicyclo[2.2.1]heptane-2-carboxylic acid instead of tert-butyl N-[(3-internal)-8-azabicyclo[3.2.1]octan-3-yl]carbamate Acid ester to obtain the title compound.

實施例83　4-[5-(3,7-二氮雜螺[3.5]壬烷-7-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　3,7-二氮雜螺[3.5]壬烷-3-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 83" 4-[5-(3,7-diazaspiro[3.5]nonane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile is based on Example 22 (steps 1 to 4), by using tert-butyl 3,7-diazaspiro[3.5]nonane-3-carboxylic acid Instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate, the title compound was obtained.

實施例84　4-[5-(2,7-二氮雜螺[3.5]壬烷-2-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　2,7-二氮雜螺[3.5]壬烷-7-羧酸 鹽酸鹽來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 84 　 4-[5-(2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl]benzene The synthesis of yl]-2-fluoro-benzonitrile is based on Example 22 (steps 1 to 4), by using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylic acid Hydrochloride instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例85　4-[5-[(1R,4R)-2,5-二氮雜雙環[2.2.1]庚烷-2-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基-(1R,4R)-2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 85 "4-[5-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]-2-[2-fluoro-4-(2-methoxy The synthesis of phenylethyl)phenyl]phenyl)-2-fluoro-benzonitrile is based on Example 22 (Steps 1~4), by using tertiary butyl-(1R,4R)-2,5 -Diazabicyclo[2.2.1]heptane-2-carboxylic acid instead of tert-butyl N-[(3-internal)-8-azabicyclo[3.2.1]octane-3-yl]amine Formate to obtain the title compound.

實施例86　2-氟-4-[2-[2-氟-4-(2-甲氧基乙基)苯基]-5-[(1S,4S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-羰基]苯基]苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用(1S,4S)-2-甲基-2,5-二氮雜雙環[2.2.1]庚烷來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 86 "2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(1S,4S)-5-methyl-2,5- The synthesis of diazabicyclo[2.2.1]heptane-2-carbonyl]phenyl]benzonitrile is based on Example 22 (Steps 1~4), by using (1S,4S)-2-methyl -2,5-diazabicyclo[2.2.1]heptane instead of tertiary butyl N-[(3-internal)-8-azabicyclo[3.2.1]octan-3-yl]aminomethyl Acid ester to obtain the title compound.

實施例87　2-氟-4-[2-[2-氟-4-(2-甲氧基乙基)苯基]-5-[(1R,4R)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-羰基]苯基]苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用(1R,4R)-2-甲基-2,5-二氮雜雙環[2.2.1]庚烷來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 87 "2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(1R,4R)-5-methyl-2,5- The synthesis of diazabicyclo[2.2.1]heptane-2-carbonyl]phenyl]benzonitrile is based on Example 22 (steps 1 to 4), by using (1R,4R)-2-methyl -2,5-diazabicyclo[2.2.1]heptane instead of tertiary butyl N-[(3-internal)-8-azabicyclo[3.2.1]octan-3-yl]aminomethyl Acid ester to obtain the title compound.

實施例88　4-[5-(3,8-二氮雜雙環[3.2.1]辛烷-3-羰基)-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成　以實施例22(步驟1~4)為準，藉由使用第三丁基　3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 88 　 4-[5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl ]Phenyl]-2-fluoro-benzonitrile was synthesized in accordance with Example 22 (steps 1 to 4) by using tert-butyl 3,8-diazabicyclo[3.2.1]octane- The 8-carboxylic acid replaces the tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例89　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1,3-苯并噻唑-5-基)苯基]-2-氟-苯甲腈之合成　以實施例16(步驟1~3)為準，藉由使用1,3-苯并噻唑-5-基硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 89 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,3-benzothiazol-5-yl)phenyl]-2-fluoro-benzyl The synthesis of nitrile was based on Example 16 (steps 1 to 3), and the title compound was obtained by using 1,3-benzothiazol-5-ylboronic acid instead of p-tolylboronic acid.

實施例90　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1-甲基吡唑并[3,4-b]吡啶-5-基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用(1-甲基吡唑并[3,4-b]吡啶-5-基)硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 90 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)phenyl ]-2-Fluoro-benzonitrile was synthesized in accordance with Example 16 (Steps 1~3) by using (1-methylpyrazolo[3,4-b]pyridin-5-yl)boronic acid Instead of p-tolylboronic acid, the title compound was obtained.

實施例91　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1-甲基苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-1-甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 91 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylbenzimidazol-5-yl)phenyl]-2-fluoro-benzyl The synthesis of nitrile is based on Example 37 (Steps 1~3), by using 5-bromo-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2- Methyl-propan-2-ol to obtain the title compound.

實施例92　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1-甲基吲唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用(1-甲基吲唑-5-基)硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 92 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylindazol-5-yl)phenyl]-2-fluoro-benzonitrile The synthesis was based on Example 16 (Steps 1 to 3), and the title compound was obtained by using (1-methylindazol-5-yl)boronic acid instead of p-tolylboronic acid.

實施例93　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2-甲基吲唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)吲唑來代替對甲苯基硼酸，而得到標題化合物。Example 93 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-methylindazol-5-yl)phenyl]-2-fluoro-benzonitrile The synthesis is based on Example 16 (Steps 1~3), by using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxolone Alk-2-yl)indazole was substituted for p-tolylboronic acid to obtain the title compound.

實施例94　4-[5-[(3S)-3-胺基吡咯啶-1-硫代羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例2為準，藉由使用實施例20(步驟3)所得到的4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(對甲苯基)苯基]苯甲腈，而得到標題化合物。Example 94 　 4-[5-[(3S)-3-aminopyrrolidine-1-thiocarbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl ]-2-Fluoro-benzonitrile was synthesized in accordance with Example 2. By using the 4-[5-[(3S)-3-aminopyrrolidine-1- obtained in Example 20 (Step 3) Carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile 4-[5-[(3S)-3-aminopyrrole Pyridin-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile to obtain the title compound.

實施例95　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-6-氟-1-甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 95 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzimidazol-5-yl)phenyl]-2 -The synthesis of fluoro-benzonitrile is based on Example 37 (Steps 1~3), by using 5-bromo-6-fluoro-1-methyl-benzimidazole instead of 1-(4-bromo-3) -Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例96　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成(步驟1)　將實施例37(步驟1)所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於1,4-二噁烷0.5mL中。於室溫添加5-溴-6-氟-1-甲基-苯并三唑 9.7mg、PdCl2 (dppf)　1.0mg、磷酸三鉀 18mg，於微波反應裝置中在125℃下攪拌30分鐘。添加乙酸乙酯，裝入NH矽膠中，以乙酸乙酯/甲醇洗淨。蒸餾去除溶劑，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-苯并三唑-5-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 96 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl)phenyl]- Synthesis of 2-fluoro-benzonitrile (Step 1) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro- (Phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-yl)amine 15 mg of formate was dissolved in 0.5 mL of 1,4-dioxane. 9.7 mg of 5-bromo-6-fluoro-1-methyl-benzotriazole, 1.0 mg of PdCl 2 (dppf), and 18 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125° C. for 30 minutes in a microwave reactor. Add ethyl acetate, put it into NH silica gel, and wash with ethyl acetate/methanol. The solvent is distilled off to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-benzene) Triazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-苯并三唑-5-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 15mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1- 15 mg of methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例97　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(4-氟苯基)苯基]苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用1-溴-4-氟苯5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 97 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-fluorophenyl)phenyl] The synthesis of benzonitrile was based on Example 23 (steps 1 to 3), and the title compound was obtained by using 1-bromo-4-fluorobenzene 5-bromo-6-fluoro-1-methyl-indole.

實施例98　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(4-氯苯基)苯基]苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用1-溴-4-氯-苯5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 98 "4-[5-[(3-Exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-chlorophenyl)phenyl] The synthesis of benzonitrile was based on Example 23 (Steps 1~3), and the title compound was obtained by using 1-bromo-4-chloro-benzene 5-bromo-6-fluoro-1-methyl-indole .

實施例99　[(3S)-3-胺基吡咯啶-1-基]-[3-(4-硝基苯基)-4-(對甲苯基)苯基]甲酮之合成以實施例19(步驟1~5)為準，藉由使用1-溴-4-硝基-苯4-溴-2,6-二氟-苯甲腈，而得到標題化合物。Example 99 The synthesis of [(3S)-3-aminopyrrolidin-1-yl]-[3-(4-nitrophenyl)-4-(p-tolyl)phenyl]methanone Take Example 19 (Steps 1 to 5) are the standard, and the title compound is obtained by using 1-bromo-4-nitro-benzene 4-bromo-2,6-difluoro-benzonitrile.

實施例100　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[6-(二甲基胺基)-3-吡啶基]苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-N,N-二甲基吡啶-2-胺來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 100 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[6-(dimethylamino)-3-pyridyl]phenyl]-2-fluoro -The synthesis of benzonitrile is based on Example 37 (Steps 1~3), by using 5-bromo-N,N-dimethylpyridin-2-amine instead of 1-(4-bromo-3-fluoro -Phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例101　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1-甲基苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-1-甲基-苯并三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 101 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylbenzotriazol-5-yl)phenyl]-2-fluoro-benzene The synthesis of carbonitrile was based on Example 37 (Steps 1~3), by using 5-bromo-1-methyl-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)- 2-Methyl-propan-2-ol to obtain the title compound.

實施例102　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(6,7-二氟-1-甲基-苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-6,7-二氟-1-甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 102 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6,7-difluoro-1-methyl-benzimidazol-5-yl)phenyl ]-2-Fluoro-benzonitrile was synthesized according to Example 37 (Steps 1~3), and 5-bromo-6,7-difluoro-1-methyl-benzimidazole was used instead of 1- (4-Bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例103　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1,2-二甲基苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-1,2-二甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 103 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,2-dimethylbenzimidazol-5-yl)phenyl]-2-fluoro -The synthesis of benzonitrile is based on Example 37 (steps 1 to 3), and 5-bromo-1,2-dimethyl-benzimidazole is used instead of 1-(4-bromo-3-fluoro- (Phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例104　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(2-萘基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用2-溴萘來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 104 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-naphthyl)phenyl]- The synthesis of 2-fluoro-benzonitrile was based on Example 23 (steps 1 to 3), and the title was obtained by using 2-bromonaphthalene instead of 5-bromo-6-fluoro-1-methyl-indole Compound.

實施例105　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(8-氟-7-喹啉基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用7-溴-8-氟喹啉來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 105 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(8-fluoro-7-quinolinyl )Phenyl]-2-fluoro-benzonitrile was synthesized according to Example 23 (steps 1~3), by using 7-bromo-8-fluoroquinoline instead of 5-bromo-6-fluoro-1 -Methyl-indole to obtain the title compound.

實施例106　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(4-甲基-2,3-二氫-1,4-苯并氧氮雜芑7-基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用7-溴-4-甲基-3,4-二氫-2H-苯并[b][1,4]氧氮雜芑來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 106 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-methyl-2,3- The synthesis of dihydro-1,4-benzoxazepine (7-yl)phenyl]-2-fluoro-benzonitrile is based on Example 23 (steps 1 to 3), by using 7-bromo- 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazepine replaces 5-bromo-6-fluoro-1-methyl-indole to obtain the title compound .

實施例107　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(7-苯醌基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用7-溴喹啉來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 107 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(7-benzoquinonyl)phenyl] The synthesis of -2-fluoro-benzonitrile is based on Example 23 (steps 1 to 3), by using 7-bromoquinoline instead of 5-bromo-6-fluoro-1-methyl-indole, and The title compound is obtained.

實施例108　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用5-溴-6-氟-1-甲基-苯并咪唑來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 108 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- The synthesis of benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile was based on Example 23 (steps 1 to 3), by using 5-bromo-6-fluoro-1-methyl- Benzimidazole was substituted for 5-bromo-6-fluoro-1-methyl-indole to obtain the title compound.

實施例109　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用5-溴-6-氟-1-甲基-苯并三唑來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 109 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- The synthesis of benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile is based on Example 23 (steps 1 to 3), by using 5-bromo-6-fluoro-1-methyl -Benzotriazole instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

實施例110　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(4-氟-1-甲基-吲唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用5-溴-4-氟-1-甲基-吲唑來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 110 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-fluoro-1-methyl- Indazol-5-yl)phenyl]-2-fluoro-benzonitrile was synthesized in accordance with Example 23 (steps 1 to 3) by using 5-bromo-4-fluoro-1-methyl-indyl Instead of 5-bromo-6-fluoro-1-methyl-indole, azole gave the title compound.

實施例111　4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(2-甲基吲唑-5-基)苯基]苯甲腈之合成以實施例23(步驟1~3)為準，藉由使用5-溴-2-甲基-2H-吲唑來代替5-溴-6-氟-1-甲基-吲哚，而得到標題化合物。Example 111 　 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-methylindazole-5- The synthesis of phenyl)benzonitrile is based on Example 23 (Steps 1~3), by using 5-bromo-2-methyl-2H-indazole instead of 5-bromo-6-fluoro-1 -Methyl-indole to obtain the title compound.

實施例112　2-氟-4-[2-[2-氟-4-(2-甲氧基乙基)苯基]-5-[(3-外)-3-(異丙基胺基)-8-氮雜雙環[3.2.1]辛烷-8-羰基]苯基]苯甲腈之合成於25℃在實施例26(步驟2)所得到的4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之二氯甲烷 0.05mL溶液中添加丙酮 0.002mL，接著添加NaBH(OAc)3 8.45mg，於室溫攪拌1小時。添加MeOH，並蒸餾去除溶劑後、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 112 2-fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(3-exo)-3-(isopropylamino) Synthesis of -8-azabicyclo[3.2.1]octane-8-carbonyl]phenyl]benzonitrile The 4-[5-[(3-external) obtained in Example 26 (Step 2) at 25°C )-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]- To the 0.05 mL solution of 2-fluoro-benzonitrile in dichloromethane, 0.002 mL of acetone was added, and then 8.45 mg of NaBH(OAc) 3 was added, and the mixture was stirred at room temperature for 1 hour. After adding MeOH and distilling off the solvent, the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例113　2-氟-4-[2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]-5-[(3-外)-3-(異丙基胺基)-8-氮雜雙環[3.2.1]辛烷-8-羰基]苯基]苯甲腈之合成以實施例112為準，藉由使用實施例28(步驟3)所得到的4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈來代替4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈，而得到標題化合物。Example 113 "2-Fluoro-4-[2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]-5-[(3-exo)-3-(isopropyl Amino)-8-azabicyclo[3.2.1]octane-8-carbonyl]phenyl]benzonitrile was synthesized in accordance with Example 112, and obtained by using Example 28 (Step 3) 4-[5-[(3-Ex)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2 -Methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile instead of 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1] Octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile to obtain the title compound.

實施例114　4-[5-[(3S)-3-(乙基胺基)吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成(步驟1)將實施例96(步驟1)所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(6-氟-1-甲基-苯并三唑-5-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 10mg溶解於THF 0.5mL中。於室溫添加氫化鈉 0.85mg，接著添加碘乙烷 5.58mg、於50℃徹夜攪拌、蒸餾去除溶劑，藉此得到(S)、第三丁基　(1-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-3-羰基)吡咯啶-3-基)(乙基)胺甲酸酯。不純化而用於下一步驟。Example 114 　 4-[5-[(3S)-3-(ethylamino)pyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl) Synthesis of phenyl]-2-fluoro-benzonitrile (step 1) The tertiary butyl N-[(3S)-1-[3-(4-cyano- 3-Fluoro-phenyl)-4-(6-fluoro-1-methyl-benzotriazol-5-yl)benzoyl)pyrrolidin-3-yl)carbamate 10mg dissolved in THF 0.5 mL in. 0.85 mg of sodium hydride was added at room temperature, followed by 5.58 mg of ethyl iodide, stirred overnight at 50°C, and the solvent was distilled off to obtain (S), tertiary butyl (1-(4'-cyano-3' -Fluoro-6-(6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-3-carbonyl ) Pyrrolidin-3-yl)(ethyl)carbamate. It was used in the next step without purification.

(步驟2)以實施例26(步驟2)為準，藉由使用、前述步驟1所得到的(S)、第三丁基　(1-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-3-羰基)吡咯啶-3-基)(乙基)胺甲酸酯來代替[(3-外)-8-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。(Step 2) Based on Example 26 (Step 2), by using the (S) obtained in the aforementioned step 1, tertiary butyl (1-(4'-cyano-3'-fluoro-6- (6-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidine-3 -Yl)(ethyl)carbamate instead of [(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2 -Methoxyethyl)phenyl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例115　2-氟-4-[2-(6-氟-1-甲基-苯并三唑-5-基)-5-[(3S)-3-(異丙基胺基)吡咯啶-1-羰基]苯基]苯甲腈之合成以實施例112為準，藉由使用、實施例96(步驟2)所得到的4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈來代替4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈，而得到標題化合物。Example 115 "2-Fluoro-4-[2-(6-fluoro-1-methyl-benzotriazol-5-yl)-5-[(3S)-3-(isopropylamino)pyrrolidine The synthesis of -1-carbonyl]phenyl]benzonitrile is based on Example 112, by using the 4-[5-[(3S)-3-aminopyrrolidine obtained in Example 96 (Step 2) -1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile instead of 4-[5-[(3-外)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]- 2-Fluoro-benzonitrile to obtain the title compound.

實施例116　4-[5-[(3S)-3-(環丁基胺基)吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例112為準，藉由使用實施例96(步驟2)所得到的4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈來代替4-[5-[(3-外)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈，且藉由使用環丁酮來代替，而得到標題化合物。Example 116 "4-[5-[(3S)-3-(Cyclobutylamino)pyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl )Phenyl]-2-fluoro-benzonitrile was synthesized in accordance with Example 112, by using the 4-[5-[(3S)-3-aminopyrrolidine obtained in Example 96 (Step 2) -1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile instead of 4-[5-[(3-外)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]- 2-Fluoro-benzonitrile, and by using cyclobutanone instead, the title compound was obtained.

實施例117　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1-甲基吲哚啉-5-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-1-甲基-吲哚啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 117 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylindolin-5-yl)phenyl]-2-fluoro-benzyl The synthesis of nitrile is based on Example 37 (Steps 1~3), by using 5-bromo-1-methyl-indoline instead of 1-(4-bromo-3-fluoro-phenyl)-2- Methyl-propan-2-ol to obtain the title compound.

實施例118　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(4-甲基-2,3-二氫-1,4-苯并氧氮雜芑7-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用7-溴-4-甲基-3,4-二氫-2H-苯并[b][1,4]氧氮雜芑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 118 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-methyl-2,3-dihydro-1,4-benzoxazepine The synthesis of 7-yl)phenyl]-2-fluoro-benzonitrile is based on Example 37 (steps 1~3), by using 7-bromo-4-methyl-3,4-dihydro-2H -Benzo[b][1,4]oxazepine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例119　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(3-甲基-2-側氧基-1,3-苯并噁唑-6-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用6-溴-3-甲基-1,3-苯并噁唑-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 119 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-methyl-2-oxo-1,3-benzoxazole-6- The synthesis of phenyl)-2-fluoro-benzonitrile is based on Example 37 (Steps 1~3), by using 6-bromo-3-methyl-1,3-benzoxazole-2 -Ketone instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例120　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(3-甲基-2-側氧基-1,3-苯并噻唑-6-基)苯基]-2-氟-苯甲腈之合成以實施例37(步驟1~3)為準，藉由使用6-溴-3-甲基-1,3-苯并噻唑-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 120 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-methyl-2-oxo-1,3-benzothiazol-6-yl )Phenyl]-2-fluoro-benzonitrile was synthesized according to Example 37 (Steps 1~3) by using 6-bromo-3-methyl-1,3-benzothiazol-2-one Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the title compound was obtained.

實施例121　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(2,3-二氫-1,4-苯并二噁嗪-6-基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用2,3-二氫-1,4-苯并二噁烷-6-基硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 121 　 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2,3-dihydro-1,4-benzodioxazine-6-yl)benzene The synthesis of yl]-2-fluoro-benzonitrile was based on Example 16 (steps 1 to 3), by using 2,3-dihydro-1,4-benzodioxane-6-ylboronic acid Instead of p-tolylboronic acid, the title compound was obtained.

實施例122　4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-(1,3-苯并二噁唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例16(步驟1~3)為準，藉由使用1,3-苯并二噁唑-5-基硼酸來代替對甲苯基硼酸，而得到標題化合物。Example 122 "4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,3-benzodiaxazol-5-yl)phenyl]-2-fluoro- The synthesis of benzonitrile was based on Example 16 (steps 1 to 3), and the title compound was obtained by using 1,3-benzodiaxazol-5-ylboronic acid instead of p-tolylboronic acid.

實施例123　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-吲哚-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6-氟-1-甲基-吲哚來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 123 　 4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- The synthesis of indol-5-yl)phenyl]-2-fluoro-benzonitrile was based on Example 41 (steps 1 to 5), by using 5-bromo-6-fluoro-1-methyl-indole Dole was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例124　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-吲唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6-氟-1-甲基-吲唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 124 　 4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- Indazol-5-yl)phenyl]-2-fluoro-benzonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 5-bromo-6-fluoro-1-methyl-indyl Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol with azole, the title compound was obtained.

實施例125　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-苯并三唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6-氟-1-甲基-苯并三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 125 　 4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- The synthesis of benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 5-bromo-6-fluoro-1-methyl -Benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例126　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6,7-二氟1-甲基-苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6,7-二氟-1-甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 126 "4-[5-[(3-Intra)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6,7-difluoro-1-methyl The synthesis of phenyl-benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 5-bromo-6,7-difluoro- 1-Methyl-benzimidazole was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例127　4-[5-[(3-外)-3-胺基-9-氮雜雙環[3.3.1]壬烷-9-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　N-[(3-外)-9-氮雜雙環[3.3.1]壬烷-3-基]胺甲酸酯來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 127 　 4-[5-[(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carbonyl]-2-[2-fluoro-4-(2- The synthesis of methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile is based on Example 22 (steps 1~4), by using tertiary butyl N-[(3-exo) -9-azabicyclo[3.3.1]nonan-3-yl]carbamate instead of tertiary butyl N-[(3-internal)-8-azabicyclo[3.2.1]octane- 3-yl] carbamate to obtain the title compound.

實施例128　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(4-甲基-2,3-二氫-1,4-苯并氧氮雜芑-7-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用7-溴-4-甲基-3,4-二氫-2H-苯并[b][1,4]氧氮雜芑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 128 　 4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-methyl-2,3- The synthesis of dihydro-1,4-benzoxazepin-7-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 7-bromo -4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazepine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl -Propan-2-ol to obtain the title compound.

實施例129　4-[5-[(3-內)-3-胺基-9-氮雜雙環[3.3.1]壬烷-9-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　N-[(3-內)-9-氮雜雙環[3.3.1]壬烷-3-基]胺甲酸酯來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 129 "4-[5-[(3-Ino)-3-amino-9-azabicyclo[3.3.1]nonane-9-carbonyl]-2-[2-fluoro-4-(2- The synthesis of methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile is based on Example 22 (steps 1 to 4), by using tertiary butyl N-[(3-内) -9-azabicyclo[3.3.1]nonan-3-yl]carbamate instead of tertiary butyl N-[(3-internal)-8-azabicyclo[3.2.1]octane- 3-yl] carbamate to obtain the title compound.

實施例130　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(6-氟-1-甲基-苯并咪唑-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6-氟-1-甲基-苯并咪唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 130 "4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro-1-methyl- The synthesis of benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 5-bromo-6-fluoro-1-methyl- Benzimidazole was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例131　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[6-(二甲基胺基)-3-吡啶基]苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-N,N-二甲基吡啶-2-胺來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 131 　 4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[6-(dimethylamino) The synthesis of -3-pyridyl]phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 5-bromo-N,N-lutidine-2- Amine was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例132　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(1,3,3-三甲基-2-側氧基-吲哚啉-5-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-1,3,3-三甲基-吲哚啉-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 132 "4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(1,3,3-trimethyl The synthesis of -2-oxo-indolin-5-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 5-bromo-1, 3,3-Trimethyl-indolin-2-one was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例133　4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-(3-甲基-2-側氧基-1,3-苯并噻唑-6-基)苯基]-2-氟-苯甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴-3-甲基-1,3-苯并噻唑-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 133 "4-[5-[(3-Ino)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(3-methyl-2-oxo The synthesis of phenyl-1,3-benzothiazol-6-yl)phenyl]-2-fluoro-benzonitrile is based on Example 41 (steps 1 to 5), by using 6-bromo-3-methyl Substitution of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol with phenyl-1,3-benzothiazol-2-one to obtain the title compound.

實施例134　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-6-氟-1-甲基-1H-吲哚來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 134 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-methyl-1H-indol-5-yl)- The synthesis of [1,1'-biphenyl]-4-carbonitrile is based on Example 37 (steps 1~3), by using 5-bromo-6-fluoro-1-methyl-1H-indole Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the title compound was obtained.

實施例135(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-甲基-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-6-氟-1-甲基-1H-吲唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 135 (S)-5'-(3-Aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-methyl-1H-indazol-5-yl)- The synthesis of [1,1'-biphenyl]-4-carbonitrile is based on Example 37 (steps 1~3), by using 5-bromo-6-fluoro-1-methyl-1H-indazole Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the title compound was obtained.

實施例136　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6-氟-1H-吲哚　50mg溶解於DMF 0.78mL中。於室溫添加Cs 2CO3 151mg、2,2-二甲基環氧乙烷 42μL，於90℃攪拌16小時。以飽和NH4 Cl水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇。Example 136 5'-((3-Intra)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- Synthesis of (2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The 5-bromo-6- 50 mg of fluorine-1H-indole was dissolved in 0.78 mL of DMF. 151 mg of C s 2CO 3 and 42 μL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 90° C. for 16 hours. It was quenched with saturated NH 4 Cl aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propane- 2-alcohol.

(步驟2)以實施例41(步驟1~5)為準，藉由使用前述(步驟1)所得到的1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 41 (Steps 1 to 5), by using the 1-(5-bromo-6-fluoro-indol-1-yl)-2-methan obtained in the aforementioned (Step 1) Substitution of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol by propyl-propan-2-ol to obtain the title compound.

實施例137　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(1,3-二氫異苯并呋喃-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-1,3-二氫異苯并呋喃來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 137 "5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1,3-dihydroisobenzofuran -5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 5-bromo-1,3- Dihydroisobenzofuran was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例138　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(3-異丙基-2-側氧基-2,3-二氫苯并[d]噻唑-6-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將6-溴-3H-1,3-苯并噻唑-2-酮　100mg溶解於DMF 0.87mL中。於室溫添加碳酸鉀　90mg，於0℃攪拌15分鐘。於室溫添加2-溴丙烷 0.082mL，於100℃攪拌3小時。以飽和NH4 Cl水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到6-溴-3-異丙基-1,3-苯并噻唑-2-酮。Example 138 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(3-isopropyl- 2-Pendant oxy-2,3-dihydrobenzo[d]thiazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) 6-bromo-3H 100 mg of -1,3-benzothiazol-2-one was dissolved in 0.87 mL of DMF. 90 mg of potassium carbonate was added at room temperature, and the mixture was stirred at 0°C for 15 minutes. 0.082 mL of 2-bromopropane was added at room temperature, and the mixture was stirred at 100°C for 3 hours. It was quenched with saturated NH 4 Cl aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 6-bromo-3-isopropyl-1,3-benzothiazol-2-one.

(步驟2)以實施例41(步驟1~5)為準，藉由使用前述(步驟1)所得到的6-溴-3-異丙基-1,3-苯并噻唑-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 41 (Steps 1 to 5), by using the 6-bromo-3-isopropyl-1,3-benzothiazol-2-one obtained in the aforementioned (Step 1) Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the title compound was obtained.

實施例139　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(1-(第三丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-1-(第三丁基)-6-氟-1H-苯并[d][1,2,3]三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 139 "5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(tertiary butyl)-6 -Fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 41 ( Steps 1~5) shall prevail, by using 5-bromo-1-(tert-butyl)-6-fluoro-1H-benzo[d][1,2,3]triazole instead of 1-(4 -Bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例140　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(1,3-二氫異苯并呋喃-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例37(步驟1~3)為準，藉由使用5-溴-1,3-二氫異苯并呋喃來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 140 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1,3-dihydroisobenzofuran-5-yl)-3-fluoro-[1, The synthesis of 1'-biphenyl]-4-carbonitrile was based on Example 37 (steps 1 to 3), and 5-bromo-1,3-dihydroisobenzofuran was used instead of 1-(4- Bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例141　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(5-氟-3-甲基-2-側氧基-2,3-二氫苯并[d]噻唑-6-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)　將5-氟-3H-1,3-苯并噻唑-2-酮　200mg懸浮於MeCN 1mL中。於室溫添加NBS 231mg，並於室溫攪拌1小時。減壓濃縮溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到6-溴-5-氟-3H-1,3-苯并噻唑-2-酮。Example 141 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-methyl-2-oxo-2,3- Synthesis of dihydrobenzo[d]thiazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile (step 1) 　 5-fluoro-3H-1,3-benzothiazole-2 -200 mg of ketone was suspended in 1 mL of MeCN. 231 mg of NBS was added at room temperature, and stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 6-bromo-5-fluoro-3H-1,3-benzothiazol-2-one .

(步驟2)將前述(步驟1)所得到的6-溴-5-氟-3H-1,3-苯并噻唑-2-酮　100mg溶解於DMF 1.3mL中。於室溫添加碳酸鉀　84mg，於0℃攪拌15分鐘。於室溫添加碘甲烷 0.050mL，並於室溫攪拌0.5小時。以飽和NH4Cl水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到6-溴-5-氟-3-甲基-1,3-苯并噻唑-2-酮。(Step 2) Dissolve 100 mg of 6-bromo-5-fluoro-3H-1,3-benzothiazol-2-one obtained in (Step 1) in 1.3 mL of DMF. 84 mg of potassium carbonate was added at room temperature, and the mixture was stirred at 0°C for 15 minutes. 0.050 mL of methyl iodide was added at room temperature, and stirred at room temperature for 0.5 hours. It was quenched with saturated NH4Cl aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 6-bromo-5-fluoro-3-methyl-1,3-benzothiazol-2-one.

(步驟3)　以實施例37(步驟1~3)為準，藉由使用前述(步驟2)所得到的6-溴-5-氟-3-甲基-1,3-苯并噻唑-2-酮來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 3) "According to Example 37 (Steps 1 to 3), by using the 6-bromo-5-fluoro-3-methyl-1,3-benzothiazole-2 obtained in the aforementioned (Step 2) -Ketone instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例142　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6-氟-1H-吲唑　94mg溶解於DMF 1.5mL中。於室溫添加碳酸銫　285mg、2,2-二甲基環氧乙烷 0.078mL，於90℃攪拌16小時。以飽和NH4 Cl水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇。Example 142 5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- Synthesis of (2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The 5-bromo-6- 94 mg of fluoro-1H-indazole was dissolved in 1.5 mL of DMF. 285 mg of cesium carbonate and 0.078 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 90°C for 16 hours. It was quenched with saturated NH 4 Cl aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propane- 2-alcohol.

(步驟2)以實施例41(步驟1~5)為準，藉由使用前述(步驟1)所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) According to Example 41 (Steps 1 to 5), by using the 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methan obtained in the aforementioned (Step 1) Substitution of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol by propyl-propan-2-ol to obtain the title compound.

實施例143　4-[5-[(1S,3R,4R)-rel-3-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基]-2-[2-氟-4-(2-甲氧基乙基)苯基]苯基]-2-氟-苯甲腈之合成(步驟1)將第三丁基　(1S,3R,4R)-rel-3-胺基-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯 50mg溶解於THF 1.2mL中。於0℃添加TEA 0.066mL、2-硝基苯磺醯氯 57mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於4當量濃度鹽酸-乙酸乙酯溶液2mL中，於室溫攪拌30分鐘。減壓濃縮反應液，而得到N-[(1S,3R,4R)-rel-7-氮雜雙環[2.2.1]庚烷-3-基]-2-硝基苯磺醯胺 鹽酸鹽。Example 143 "4-[5-[(1S,3R,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-2-[2-fluoro-4 -(2-Methoxyethyl)phenyl)phenyl)-2-fluoro-benzonitrile synthesis (step 1) The tertiary butyl (1S,3R,4R)-rel-3-amino- 50 mg of 7-azabicyclo[2.2.1]heptane-7-carboxylate was dissolved in 1.2 mL of THF. 0.066 mL of TEA and 57 mg of 2-nitrobenzenesulfonyl chloride were added at 0°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 2 mL of a 4 equivalent hydrochloric acid-ethyl acetate solution, and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain N-[(1S,3R,4R)-rel-7-azabicyclo[2.2.1]heptan-3-yl]-2-nitrobenzenesulfonamide hydrochloride .

(步驟2)以實施例22(步驟3)為準，藉由使用、前述(步驟1)所得到的N-[(1S,3R,4R)-rel-7-氮雜雙環[2.2.1]庚烷-3-基]-2-硝基苯磺醯胺 鹽酸鹽來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2-硝基苯磺醯胺。(Step 2) Based on Example 22 (Step 3), by using the N-[(1S,3R,4R)-rel-7-azabicyclo[2.2.1] obtained in the aforementioned (Step 1) Heptan-3-yl]-2-nitrobenzenesulfonamide hydrochloride instead of tert-butyl N-[(3-internal)-8-azabicyclo[3.2.1]octane-3-yl ] Carbamate to obtain N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-( 2-Methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2-nitrobenzenesulfonamide.

(步驟3)將前述(步驟2)所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2-硝基苯磺醯胺 20mg溶解於DMF 0.5mL中。於室溫添加K2 CO3 21mg、4-巰基苯甲酸 12mg，於40℃攪拌12小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(2- Fluoro-4-(2-methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2-nitrobenzenesulfonamide 20mg dissolved In DMF 0.5mL. 21 mg of K 2 CO 3 and 12 mg of 4-mercaptobenzoic acid were added at room temperature, and the mixture was stirred at 40°C for 12 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例144　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’’,3,3’’-三氟-4’’-甲基-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用1-溴-2,3-二氟-4-甲基-苯來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 144 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'',3,3''-trifluoro-4 The synthesis of''-methyl-[1,1':2',1''-terphenyl]-4-carbonitrile is based on Example 41 (steps 1 to 5), by using 1-bromo- 2,3-Difluoro-4-methyl-benzene was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例145　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(6,7-二氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 200mg、5-溴-6,7-二氟-1-甲基-苯并三唑 129mg溶解於1,4-二噁烷1.74mL中。於室溫添加Pd(dba)2 16.0mg、X-Phos 26.5mg、磷酸三鉀 221mg，於微波反應裝置中在125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：乙酸乙酯/己烷)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 145 5'-((3-Intra)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-methyl The synthesis of phenyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile (step 1) will be implemented Example 41 The tertiary butyl N-[(3-internal)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 200mg 129 mg of 5-bromo-6,7-difluoro-1-methyl-benzotriazole was dissolved in 1.74 mL of 1,4-dioxane. Pd(dba) 2 16.0 mg, X-Phos 26.5 mg, and tripotassium phosphate 221 mg were added at room temperature, and the mixture was stirred at 125° C. for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane) to obtain tertiary butyl N-[(3-内)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-8-azabicyclo[3.2.1]octane-3 -Base] carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 210mg溶解於MeOH 1.60mL中。於室溫添加4當量濃度鹽酸-乙酸乙酯溶液 2.40mL，並於室溫攪拌1小時。減壓濃縮反應液，並蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7- Difluoro-1-methyl-benzotriazol-5-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 210mg dissolved in MeOH 1.60mL in. Add 2.40 mL of 4 equivalents of hydrochloric acid-ethyl acetate solution at room temperature, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例146　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 60mg、實施例136步驟1所得到的1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇 48.1mg溶解於1,4-二噁烷0.50mL中。於室溫添加Pd(dba)2 3.22mg、X-Phos 5.34mg、磷酸三鉀 71.4mg，在微波反應裝置中於125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 146 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)- Synthesis of 1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The tertiary butyl N-[(3S)- 1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- (Yl)benzoyl)pyrrolidin-3-yl)carbamate 60mg, 1-(5-bromo-6-fluoro-indol-1-yl)-2-methan obtained in step 1 of Example 136 48.1 mg of propyl-propan-2-ol was dissolved in 0.50 mL of 1,4-dioxane. Pd(dba)2 3.22 mg, X-Phos 5.34 mg, and tripotassium phosphate 71.4 mg were added at room temperature, and the mixture was stirred at 125°C for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-[6-Fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 68.0mg溶解於MeOH 1.0mL中。於室溫添加12當量濃度鹽酸 1.0mL，並於室溫攪拌1小時。添加2當量濃度氫氧化鈉水溶液 6.00mL、氯仿，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1- (2-Hydroxy-2-methyl-propyl)indol-5-yl]benzyl]pyrrolidin-3-yl]carbamate 68.0 mg was dissolved in 1.0 mL of MeOH. 1.0 mL of 12 equivalents of hydrochloric acid was added at room temperature, and stirred at room temperature for 1 hour. Add 6.00 mL of 2 equivalent sodium hydroxide aqueous solution and chloroform, wash with water and saturated saline in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例147　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 70mg、實施例142步驟1所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇 56.3mg溶解於1,4-二噁烷0.50mL中。於室溫添加Pd(dba)2 3.76mg、X-Phos 6.23mg、磷酸三鉀 83.3mg，於微波反應裝置中在125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 147 (S)-5'-(3-Aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)- Synthesis of 1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The tertiary butyl N-[(3S)-1 obtained in Example 37 Step 1 -[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Benzoyl)pyrrolidin-3-yl)carbamate 70mg, 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl obtained in step 1 of Example 142 -56.3 mg of propane-2-ol was dissolved in 0.50 mL of 1,4-dioxane. Pd(dba) 2 3.76 mg, X-Phos 6.23 mg, and 83.3 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125° C. for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-[6-Fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 70.0mg溶解於MeOH 1.0mL中。於室溫添加12當量濃度鹽酸 1.0mL，並於室溫攪拌1小時。添加2當量濃度氫氧化鈉水溶液 6.00mL、氯仿，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1- (2-Hydroxy-2-methyl-propyl)indazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate 70.0 mg was dissolved in 1.0 mL of MeOH. 1.0 mL of 12 equivalents of hydrochloric acid was added at room temperature, and stirred at room temperature for 1 hour. Add 6.00 mL of 2 equivalent sodium hydroxide aqueous solution and chloroform, wash with water and saturated saline in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例148　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(喹噁啉-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴喹噁啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 148 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(quinoxaline-6- Yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), and 6-bromoquinoxaline was used instead of 1-(4-bromo- 3-Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例149　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(異喹啉-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴異喹啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 149 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(isoquinoline-6- Base)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 6-bromoisoquinoline instead of 1-(4-bromo- 3-Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例150　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(異喹啉-7-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用7-溴異喹啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 150 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(isoquinoline-7- Base)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 7-bromoisoquinoline instead of 1-(4-bromo- 3-Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例151　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(喹啉-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴喹啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 151 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(quinolin-6-yl )-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 6-bromoquinoline instead of 1-(4-bromo-3- Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例152　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(喹唑啉-7-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用7-溴喹唑啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 152 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(quinazoline-7- Base)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 7-bromoquinazoline instead of 1-(4-bromo- 3-Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例153　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(喹唑啉-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴喹唑啉來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 153 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(quinazoline-6- Base)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), and 6-bromoquinazoline was used instead of 1-(4-bromo- 3-Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例154　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(酞嗪-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴酞嗪來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 154 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(phthalazin-6-yl )-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (Steps 1~5), by using 6-bromophthalazine instead of 1-(4-bromo-3- Fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例155　5’-((1R,2R,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-甲氧基乙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈-異構物-B之合成(步驟1)將第三丁基　(1S,3R,4R)-rel-3-胺基-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯 550mg溶解於THF 13.0mL中。於0℃添加TEA 0.720mL、2,4-二硝基苯磺醯氯 829mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯。Example 155 ``5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'',3-difluoro-4 ''-(2-Methoxyethyl)-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-B synthesis (step 1) 550 mg of butyl (1S, 3R, 4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate was dissolved in 13.0 mL of THF. 0.720 mL of TEA and 829 mg of 2,4-dinitrobenzenesulfonyl chloride were added at 0°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl(1S,3R,4R)-rel-3-[(2,4-dinitrobenzene) Yl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7-carboxylate.

(步驟2)使用SFC將前述步驟1所得到的第三丁基　(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯 440mg進行掌性離析(裝置：Thar SFC prep 80 system、管柱：CHIRALPAK IE 20x250 mm、流速：50g/min、移動相：CO2/MeOH＝90/10)，而分別得到(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-A(faster異構物)、(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-B(slower異構物)。(Step 2) Use SFC to convert the tertiary butyl (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido]-7-nitrogen obtained in step 1 above Heterobicyclo[2.2.1]heptane-7-carboxylate 440mg was subjected to palm separation (device: Thar SFC prep 80 system, column: CHIRALPAK IE 20x250 mm, flow rate: 50g/min, mobile phase: CO2/MeOH= 90/10), and (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido]-7-azabicyclo[2.2.1]heptane -7-carboxylate-isomer-A (faster isomer), (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido]-7 -Azabicyclo[2.2.1]heptane-7-carboxylate-isomer-B (slower isomer).

又，藉由以下之HPLC條件進行各異構物的分析。管柱：CHIRALPAK　IE　4.6x150　mm移動相：己烷(0.1%三乙基胺)/乙醇＝85/15流速：1.0mL/min各異構物之保持時間：(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-A：10.903　min(faster異構物)(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-B：14.028　min(slower異構物)(步驟3) 將前述步驟2所得到的(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-B 200mg溶解於乙酸乙酯 1.00mL中，於室溫添加4當量濃度鹽酸-乙酸乙酯溶液 2.00mL，並於室溫攪拌2小時。減壓濃縮反應液，藉此得到N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽。In addition, the analysis of each isomer was performed under the following HPLC conditions. Column: CHIRALPAK　IE　4.6x150　mm Mobile phase: hexane (0.1% triethylamine)/ethanol=85/15 Flow rate: 1.0mL/min The retention time of each isomer: (1S, 3R, 4R)-rel -3-[(2,4-Dinitrophenyl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-A: 10.903　min(faster Isomer) (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7-carboxy Ester-isomer-B: 14.028　min (slower isomer) (step 3) The (1S,3R,4R)-rel-3-[(2,4-dinitrobenzene) obtained in step 2 above Yl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-B 200mg was dissolved in 1.00mL of ethyl acetate, and 4 equivalents of hydrochloric acid were added at room temperature -2.00 mL of ethyl acetate solution, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-dinitrobenzenesulfonate Amine-isomer-B hydrochloride.

(步驟4)將實施例22步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸 8mg、前述步驟3所得到的N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 8.47mg溶解於THF 0.30mL中。於室溫添加TEA 8.49μL、HATU 15.5mg，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 4) The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl] obtained in step 2 of Example 22 8mg of benzoic acid, N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-dinitrobenzenesulfon obtained in step 3 above 8.47 mg of amide-isomer-B hydrochloride was dissolved in 0.30 mL of THF. 8.49 μL of TEA and 15.5 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3- Fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl] -2,4-Dinitrobenzenesulfonamide-isomer-B.

(步驟5)將前述步驟4所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 14.5mg溶解於DCM 1mL中。於0℃下添加巰基乙酸 2.83μL、TEA 7.49μL，於室溫攪拌2小時。添加氯仿，以4當量濃度氫氧化鈉水溶液洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(2-fluoro- 4-(2-Methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonamide- 14.5 mg of Isomer-B was dissolved in 1 mL of DCM. Add 2.83 μL of thioglycolic acid and 7.49 μL of TEA at 0°C, and stir at room temperature for 2 hours. Chloroform was added, washed with 4 equivalents of sodium hydroxide aqueous solution, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例156　5’-((1R,2R,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-甲氧基乙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈-異構物-A之合成(步驟1)將實施例155步驟2所得到的(1S,3R,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-A 200mg溶解於乙酸乙酯 1.00mL中，於室溫添加4當量濃度鹽酸-乙酸乙酯溶液 2.00mL，並於室溫攪拌2小時。減壓濃縮反應液，藉此得到N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-A鹽酸鹽。Example 156 "5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'',3-difluoro-4 ''-(2-Methoxyethyl)-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-A synthesis (step 1) 155 (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7 obtained in step 2 -Carboxylate-isomer-A 200 mg was dissolved in 1.00 mL of ethyl acetate, 2.00 mL of 4 equivalent hydrochloric acid-ethyl acetate solution was added at room temperature, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-dinitrobenzenesulfonate Amine-isomer-A hydrochloride.

(步驟2)將實施例22步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲酸 8mg、前述步驟1所得到的N-((1r,2r,4s)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-A 鹽酸鹽 8.47mg溶解於THF 0.30mL中。於室溫添加TEA 8.49μL、HATU 15.5mg，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-A。(Step 2) The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl] obtained in step 2 of Example 22 8mg of benzoic acid, N-((1r,2r,4s)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-dinitrobenzenesulfon obtained from step 1 above 8.47 mg of amide-isomer-A hydrochloride was dissolved in 0.30 mL of THF. 8.49 μL of TEA and 15.5 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3- Fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl] -2,4-Dinitrobenzenesulfonamide-Isomer-A.

(步驟3)將前述步驟2所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-甲氧基乙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-A 14.5mg溶解於DCM 1mL中。於0℃下添加巰基乙酸 2.83μL、TEA 7.49μL，於室溫攪拌2小時。添加氯仿，以4當量濃度氫氧化鈉水溶液洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(2-fluoro- 4-(2-Methoxyethyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonamide- 14.5 mg of Isomer-A was dissolved in 1 mL of DCM. Add 2.83 μL of thioglycolic acid and 7.49 μL of TEA at 0°C, and stir at room temperature for 2 hours. Chloroform was added, washed with 4 equivalents of sodium hydroxide aqueous solution, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例157　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(3-甲基咪唑并[1,5-a]吡啶-7-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用7-溴-3-甲基-咪唑并[1,5-a]吡啶來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 157 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(3-methylimidazo [1,5-a]pyridin-7-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 41 (steps 1 to 5), by using 7-bromo- Instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, 3-methyl-imidazo[1,5-a]pyridine gave the title compound.

實施例158　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(3-甲基吡唑并[1,5-a]嘧啶-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用6-溴-3-甲基-吡唑并[1,5-a]嘧啶來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 158 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(3-methylpyrazole The synthesis of and [1,5-a]pyrimidin-6-yl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 41 (steps 1 to 5), by using 6-bromo -3-Methyl-pyrazolo[1,5-a]pyrimidine was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例159　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-2-(2-羥基-2-甲基丙基)-2H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6-氟-1H-吲唑　94mg溶解於DMF 1.5mL中。於室溫添加碳酸銫　285mg、2,2-二甲基環氧乙烷 0.078mL，於90℃攪拌16小時。以飽和NH4Cl水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-吲唑-2-基)-2-甲基-丙烷-2-醇。Example 159 　 5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-2- Synthesis of (2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The 5-bromo-6- 94 mg of fluoro-1H-indazole was dissolved in 1.5 mL of DMF. 285 mg of cesium carbonate and 0.078 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 90°C for 16 hours. It was quenched with saturated NH4Cl aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-indazol-2-yl)-2-methyl-propane- 2-alcohol.

(步驟2)以實施例41(步驟1~5)為準，藉由使用前述步驟1所得到的1-(5-溴-6-氟-吲唑-2-基)-2-甲基-丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 41 (Steps 1 to 5), by using the 1-(5-bromo-6-fluoro-indazol-2-yl)-2-methyl- Propane-2-ol was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例160　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(1-乙基-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-1-乙基-6-氟-苯并三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 160 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-ethyl-6-fluoro-1H -Benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized according to Example 41 (Steps 1~5 ) Shall prevail, by using 5-bromo-1-ethyl-6-fluoro-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2- Alcohol to obtain the title compound.

實施例161　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成　(步驟1)將1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 6.20g溶解於DMF 84.0mL中。於室溫添加NBS 5.80g，並於90℃攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(4-溴-2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。Example 161 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-( 2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Carbonitrile (Step 1) Dissolve 6.20 g of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol in 84.0 mL of DMF. 5.80 g of NBS was added at room temperature, and stirred at 90°C for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-2,3-difluoro-6-nitro-anilino)-2-methyl Group-propan-2-ol.

(步驟2)將前述步驟1所得到的1-(4-溴-2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 5.67g溶解於乙醇 87.2mL中。於室溫添加氯化銨　5.67g、鐵　5.67g、水 87.2mL，於60℃徹夜攪拌。以矽藻土過濾反應液，並以乙酸乙酯洗淨。減壓濃縮濾液，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(6-胺基-4-溴-2,3-二氟-苯胺基)-2-甲基-丙烷-2-醇。(Step 2) Dissolve 5.67 g of 1-(4-bromo-2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 1 above in ethanol 87.2 mL in. At room temperature, 5.67 g of ammonium chloride, 5.67 g of iron, and 87.2 mL of water were added, and the mixture was stirred at 60°C overnight. The reaction solution was filtered with celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-amino-4-bromo-2,3-difluoro-anilino)-2-methyl Group-propan-2-ol.

(步驟3)將前述步驟2所得到的1-(6-胺基-4-溴-2,3-二氟-苯胺基)-2-甲基-丙烷-2-醇 4.36g溶解於水 28.4mL、THF 28.4mL中。於0℃添加12當量濃度鹽酸28.4mL、亞硝酸鈉 1.80g，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇。(Step 3) Dissolve 4.36 g of 1-(6-amino-4-bromo-2,3-difluoro-anilino)-2-methyl-propan-2-ol obtained in step 2 above in water 28.4 mL, THF 28.4mL. At 0°C, 28.4 mL of 12 equivalents of hydrochloric acid and 1.80 g of sodium nitrite were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2- Methyl-propan-2-ol.

(步驟4)將實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 50mg、前述步驟3所得到的1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇 39.9mg溶解於1,4-二噁烷0.50mL中。於室溫添加Pd(dba)2 2.50mg、X-Phos 4.14mg、磷酸三鉀 55.3mg，於微波反應裝置中在125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。(Step 4) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl ] 50 mg of carbamate, 39.9 mg of 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol obtained in step 3 above are dissolved In 1,4-dioxane 0.50mL. Pd(dba) 2 2.50 mg, X-Phos 4.14 mg, and 55.3 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125° C. for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3-internal)-8-[3-(4-cyano-3-fluoro-benzene) Yl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzyl]-8-azabicyclo[3.2 .1] Octan-3-yl] carbamate.

(步驟5)將前述步驟4所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 55.0mg溶解於MeOH 1.0mL中。於室溫添加12當量濃度鹽酸 1.0mL，並於室溫攪拌1小時。添加2當量濃度氫氧化鈉水溶液 6.00mL、氯仿，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 5) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7- Difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzyl]-8-azabicyclo[3.2.1]octane-3-yl] 55.0 mg of carbamate was dissolved in 1.0 mL of MeOH. 1.0 mL of 12 equivalents of hydrochloric acid was added at room temperature, and stirred at room temperature for 1 hour. Add 6.00 mL of 2 equivalent sodium hydroxide aqueous solution and chloroform, wash with water and saturated saline in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例162　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 100mg、實施例161步驟3所得到的1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇 85.8mg溶解於1,4-二噁烷0.934mL中。於室溫添加Pd(dba)2 5.37mg、X-Phos 8.90mg、磷酸三鉀 119mg，於微波反應裝置中在125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 162 (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H Synthesis of -benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile (step 1) 1 The obtained tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate 100mg, 1-(5-bromo- 85.8 mg of 6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol was dissolved in 0.934 mL of 1,4-dioxane. Pd(dba) 2 5.37 mg, X-Phos 8.90 mg, and 119 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125°C for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-[6,7-Difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamic acid ester.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 99.8mg溶解於MeOH 1.0mL中。於室溫添加12當量濃度鹽酸 1.0mL，並於室溫攪拌1小時。添加2當量濃度氫氧化鈉水溶液 6.00mL、氯仿，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro 99.8 mg of -1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 1.0 mL of MeOH. 1.0 mL of 12 equivalents of hydrochloric acid was added at room temperature, and stirred at room temperature for 1 hour. Add 6.00 mL of 2 equivalent sodium hydroxide aqueous solution and chloroform, wash with water and saturated saline in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例163　2’’,3-二氟-4’’-(2-甲氧基乙基)-5’-(哌嗪-1-羰基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　哌嗪-1-羧酸酯來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 163``2'',3-Difluoro-4''-(2-methoxyethyl)-5'-(piperazine-1-carbonyl)-[1,1':2',1'' -Terphenyl]-4-carbonitrile was synthesized in accordance with Example 22 (steps 1 to 4), by using tert-butylpiperazine-1-carboxylate instead of tert-butyl N-[( 3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例164　(R)-5’-(3-胺基哌啶-1-羰基)-2’’,3-二氟-4’’-(2-甲氧基乙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　N-[(3R)-3-哌啶基]胺甲酸酯來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 164 ``(R)-5'-(3-aminopiperidine-1-carbonyl)-2'',3-difluoro-4''-(2-methoxyethyl)-[1,1 The synthesis of':2',1''-terphenyl]-4-carbonitrile is based on Example 22 (steps 1 to 4), by using tertiary butyl N-[(3R)-3-piper Substituting pyridinyl] carbamate for tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl] carbamate gave the title compound.

實施例165　5’-(4-胺基吖

Figure 107117996-A0101-12-0012-002
-1-羰基)-2’’,3-二氟-4’’-(2-甲氧基乙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成以實施例22(步驟1~4)為準，藉由使用第三丁基　N-(吖
Figure 107117996-A0101-12-0012-002
-4-基)胺甲酸酯來代替第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 165 5'-(4-amino acridine
Figure 107117996-A0101-12-0012-002
-1-carbonyl)-2``,3-difluoro-4''-(2-methoxyethyl)-[1,1':2',1''-terphenyl)-4-methyl The synthesis of nitrile is based on Example 22 (steps 1 to 4), by using tertiary butyl N-(吖
Figure 107117996-A0101-12-0012-002
-4-yl) carbamate instead of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl] carbamate to obtain the title compound .

實施例166　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈-異構物-B之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 500mg、實施例28之步驟1所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇 379mg溶解於1,4-二噁烷5.9mL中。於室溫下添加Pd(dba)2 68mg、X-Phos 113mg、磷酸三鉀 752mg，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸酯。Example 166 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'',3-difluoro-4 Synthesis of''-(2-hydroxy-2-methylpropyl)-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-B (Step 1) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxolane-2-yl)benzoate 500mg, 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2 obtained in step 1 of Example 28 -379 mg of alcohol was dissolved in 5.9 mL of 1,4-dioxane. Pd(dba) 2 68 mg, X-Phos 113 mg, and tripotassium phosphate 752 mg were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4- [2-Fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoate.

(步驟2)將前述步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸酯 300mg溶解於THF 0.9mL中。於0℃添加12當量濃度鹽酸 0.9mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸。(Step 2) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl- 300 mg of propyl)phenyl]benzoate was dissolved in 0.9 mL of THF. Add 0.9 mL of 12 equivalents of hydrochloric acid at 0°C, and stir at room temperature for 2 hours. MTBE was added, washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2 -Hydroxy-2-methyl-propyl)phenyl]benzoic acid.

(步驟3)將前述步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸 10mg、實施例155之步驟3所得到的N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 10.2mg溶解於THF 0.12mL中。於室溫添加TEA 0.014mL、HATU 18.7mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 3) The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)benzene obtained in the aforementioned step 2 Yl]benzoic acid 10mg, N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4- obtained in step 3 of Example 155 10.2 mg of dinitrobenzenesulfonamide-isomer-B hydrochloride was dissolved in 0.12 mL of THF. TEA 0.014 mL and HATU 18.7 mg were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3R,4R)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzyl]-7-azabicyclo[2.2 .1]Heptan-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

(步驟4)將前述步驟3所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 15mg溶解於DCM 0.2mL中。於0℃下添加巰基乙酸 2μL、TEA 8.6μL，於室溫攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(2-fluoro- 4-(2-Hydroxy-2-methyl-propyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzene 15 mg of sulfonamide-isomer-B was dissolved in 0.2 mL of DCM. Add 2 μL of thioglycolic acid and 8.6 μL of TEA at 0°C, and stir at room temperature for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例167　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 60mg、5-溴-6,7-二氟-1-甲基-苯并三唑 41.7mg溶解於1,4-二噁烷0.56mL中。於室溫添加Pd(dba)2 3.22mg、X-Phos 5.34mg、磷酸三鉀 71.4mg，在微波反應裝置中於125℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯。Example 167 (S)-5'-(3-Aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-methyl-1H-benzo[d][1,2 ,3]Triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) The tertiary butyl N- obtained in step 1 of Example 37 [(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxol Boran-2-yl) benzoyl) pyrrolidin-3-yl) carbamate 60 mg, 5-bromo-6,7-difluoro-1-methyl-benzotriazole 41.7 mg dissolved in 1 ,4-dioxane 0.56mL. Pd(dba) 2 3.22 mg, X-Phos 5.34 mg, and 71.4 mg of tripotassium phosphate were added at room temperature, and the mixture was stirred at 125° C. for 1 hour in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl) -4-(6,7-Difluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯 20mg溶解於TFA 0.40mL中，於室溫攪拌5分鐘。以LCMS確認反應完結之後，添加DMSO 1.60mL，並以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro 20 mg of -1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate was dissolved in 0.40 mL of TFA, and stirred at room temperature for 5 minutes. After confirming the completion of the reaction by LCMS, 1.60 mL of DMSO was added, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例168　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-丙基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例41(步驟1~5)為準，藉由使用5-溴-6-氟-1-丙基-苯并三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 168 "5'-((3-Internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- Propyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized according to Example 41 (Steps 1~5 ) Shall prevail, by using 5-bromo-6-fluoro-1-propyl-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2- Alcohol to obtain the title compound.

實施例169　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-甲氧基乙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成　(步驟1)以實施例161(步驟1~3)為準，藉由使用2,3-二氟-N-(2-甲氧基乙基)-6-硝基-苯胺來代替1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇，而得到5-溴-6,7-二氟-1-(2-甲氧基乙基)苯并三唑。Example 169 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-methoxyethyl)-1H-benzo [d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) according to Example 161 (step 1~ 3) shall prevail, by using 2,3-difluoro-N-(2-methoxyethyl)-6-nitro-aniline instead of 1-(2,3-difluoro-6-nitro- Anilino)-2-methyl-propane-2-ol to obtain 5-bromo-6,7-difluoro-1-(2-methoxyethyl)benzotriazole.

(步驟2)以實施例37(步驟1~3)為準，藉由使用前述步驟1所得到的5-溴-6,7-二氟-1-(2-甲氧基乙基)苯并三唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) According to Example 37 (Steps 1 to 3), by using the 5-bromo-6,7-difluoro-1-(2-methoxyethyl)benzo Triazole was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例170　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基乙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例37(步驟1~3)為準，藉由使用2-(5-溴-6-氟-吲哚-1-基)乙醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 170 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxyethyl)-1H-indole- The synthesis of 5-yl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 37 (Steps 1~3), by using 2-(5-bromo-6-fluoro-indole -1-yl)ethanol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例171　5’-((1R,2R,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈-異構物-B之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 2.3g、實施例136的步驟1所得到的1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇 2.02g溶解於1,4-二噁烷18.1mL中。於室溫下添加Pd(dba)2 250mg、X-Phos 414mg、磷酸三鉀 3.46g，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 40.0mL中。於0℃添加12當量濃度鹽酸 30.0mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸。Example 171 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Synthesis of fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B ( Step 1) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3) obtained in step 1 of Example 41 ,2-Dioxolpan-2-yl)benzoate 2.3g, 1-(5-bromo-6-fluoro-indol-1-yl) obtained in step 1 of Example 136 2.02 g of 2-methyl-propane-2-ol was dissolved in 18.1 mL of 1,4-dioxane. Pd(dba) 2 250 mg, X-Phos 414 mg, and 3.46 g of tripotassium phosphate were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 40.0 mL of THF. 30.0 mL of 12 equivalents of hydrochloric acid was added at 0°C, and stirred at room temperature for 2 hours. MTBE was added, washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2 -Hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid.

(步驟2)　將前述步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸 8mg、實施例155之步驟3所得到的N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 7.47mg溶解於THF 0.30mL中。於室溫添加TEA 0.00748mL、HATU 13.6mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 2) ``The 3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-(2-hydroxy-2-methyl-propyl)indole obtained in the aforementioned step 1 Dol-5-yl]benzoic acid 8mg, N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl) obtained in step 3 of Example 155 7.47 mg of 2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride was dissolved in 0.30 mL of THF. 0.00748 mL of TEA and 13.6 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3R,4R)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]-7-nitrogen Heterobicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

(步驟3)將前述步驟2所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 13.8mg溶解於DCM 1.0mL中。於0℃下添加巰基乙酸 2.49μL、TEA 7.48μL，於室溫攪拌1小時。添加氯仿、4當量濃度氫氧化鈉，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro- 1-(2-Hydroxy-2-methyl-propyl)indol-5-yl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4- 13.8 mg of dinitrobenzenesulfonamide-isomer-B was dissolved in 1.0 mL of DCM. Add 2.49 μL of thioglycolic acid and 7.48 μL of TEA at 0°C, and stir at room temperature for 1 hour. Chloroform and 4 equivalents of sodium hydroxide were added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例172　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6,7-二氟-1H-吲哚　300mg溶解於DMF 4.31mL中。於室溫添加Cs2 CO3 843mg、2,2-二甲基環氧乙烷 0.230mL，於80℃攪拌3小時。過濾反應液，並蒸餾去除溶劑。添加乙酸乙酯，飽和氯化銨水溶液、以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇。Example 172 (S)-5'-(3-Aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H -Indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) 5-bromo-6,7-difluoro-1H-indole 300mg Dissolved in 4.31mL of DMF. 843 mg of Cs 2 CO 3 and 0.230 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 80°C for 3 hours. The reaction liquid was filtered, and the solvent was distilled off. Add ethyl acetate, saturated ammonium chloride aqueous solution, washed with water, saturated brine in this order, dried with anhydrous sodium sulfate, and distilled off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl -Propane-2-ol.

(步驟2)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 210mg、前述步驟1所得到的1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇 196mg溶解於1,4-二噁烷1.65mL中。於室溫下添加Pd(dba)2 22.8mg、X-Phos 37.8mg、磷酸三鉀 316mg，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 2.63mL中。於0℃添加12當量濃度鹽酸 2.1mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸。(Step 2) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1, 210 mg of 3,2-dioxaborolan-2-yl)benzoate, 1-(5-bromo-6,7-difluoro-indol-1-yl) obtained in step 1 above 196 mg of 2-methyl-propane-2-ol was dissolved in 1.65 mL of 1,4-dioxane. Pd(dba) 2 22.8 mg, X-Phos 37.8 mg, and tripotassium phosphate 316 mg were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 2.63 mL of THF. At 0°C, 2.1 mL of 12 equivalents of hydrochloric acid was added, and stirred at room temperature for 2 hours. Add MTBE, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1 -(2-Hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid.

(步驟3)將前述步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸 30mg、第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯 13.2mg溶解於THF 0.323mL中。於室溫添加TEA 0.027mL、HATU 49.1mg，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯。(Step 3) The 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propane) obtained in the aforementioned step 2 30 mg of indol-5-yl]benzoic acid and 13.2 mg of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate were dissolved in 0.323 mL of THF. 0.027 mL of TEA and 49.1 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro- Phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]pyrrolidin-3-yl]carbamate Acid ester.

(步驟4)將前述步驟3所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]吡咯啶-3-基]胺甲酸酯 40mg溶解於MeOH 0.80mL中。於室溫添加4當量濃度鹽酸-1,4-二噁烷溶液 0.80mL，於室溫攪拌1小時。添加氯仿、2當量濃度氫氧化鈉水溶液 1.6mL，以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro 40 mg of -1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]pyrrolidin-3-yl]carbamate was dissolved in 0.80 mL of MeOH. Add 0.80 mL of 4 equivalents of hydrochloric acid-1,4-dioxane solution at room temperature, and stir at room temperature for 1 hour. Add 1.6 mL of chloroform and 2N sodium hydroxide aqueous solution, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例173　5’-(7-胺基-2-氮雜雙環[2.2.1]庚烷-2-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成將實施例171步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸 8mg溶解於THF 0.3mL中。於室溫添加第三丁基　N-(3-氮雜雙環[2.2.1]庚烷-7-基)胺甲酸酯 3.80mg、TEA 0.0075mL、HATU 13.6mg，於50℃攪拌3小時。以LCMS確認反應的完結之後，濃縮反應液。對殘渣添加TFA 0.20mL，於室溫攪拌5分鐘。以LCMS確認反應的完結之後，於反應液中添加DMSO 0.8mL，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。Example 173 "5'-(7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2 -Methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile Synthesis of 3-(4-cyano- 8 mg of 3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid was dissolved in 0.3 mL of THF. 3.80 mg of tert-butyl "N-(3-azabicyclo[2.2.1]heptane-7-yl)carbamate, 0.0075 mL of TEA, and 13.6 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 3 hours. After confirming the completion of the reaction by LCMS, the reaction liquid was concentrated. 0.20 mL of TFA was added to the residue, and the mixture was stirred at room temperature for 5 minutes. After confirming the completion of the reaction by LCMS, 0.8 mL of DMSO was added to the reaction solution, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例174　5’-(7-胺基-2-氮雜雙環[2.2.1]庚烷-2-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成(步驟1)將實施例166步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸 100mg溶解於THF 0.982mL中。於室溫添加第三丁基　N-(3-氮雜雙環[2.2.1]庚烷-7-基)胺甲酸酯 52.1mg、TEA 0.103mL、HATU 187mg，於50℃攪拌3小時。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[3-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-3-氮雜雙環[2.2.1]庚烷-7-基]胺甲酸酯。Example 174 ``5'-(7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-2'',3-difluoro-4''-(2-hydroxy-2- Synthesis of methylpropyl)-[1,1':2',1''-terphenyl]-4-carbonitrile (step 1) The 3-(4-cyano group obtained in step 2 of Example 166 100 mg of -3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid was dissolved in 0.982 mL of THF. 52.1 mg of tert-butyl "N-(3-azabicyclo[2.2.1]heptane-7-yl)carbamate, 0.103 mL of TEA, and 187 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 3 hours. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[3-[3-(4-cyano-3-fluoro-phenyl)- 4-[2-Fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzyl]-3-azabicyclo[2.2.1]heptane-7-yl]carbamate Acid ester.

(步驟2)將前述步驟1所得到的第三丁基　N-[3-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-3-氮雜雙環[2.2.1]庚烷-7-基]胺甲酸酯 30mg溶解於MeOH 0.5mL中，於室溫添加12當量濃度鹽酸 0.5mL。於室溫添加攪拌0.5小時後，添加水、2當量濃度氫氧化鈉水溶液 3.0mL。以氯仿萃取，並蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[3-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy -2-Methyl-propyl)phenyl]benzyl]-3-azabicyclo[2.2.1]heptane-7-yl]carbamate 30mg dissolved in MeOH 0.5mL, at room temperature Add 0.5 mL of 12 equivalents of hydrochloric acid. After stirring for 0.5 hour at room temperature, water and 3.0 mL of 2N sodium hydroxide aqueous solution were added. It was extracted with chloroform and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例175　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-B之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 90mg、5-溴-6,7-二氟-1-甲基-苯并三唑 68.6mg溶解於1,4-二噁烷0.71mL中。於室溫下，添加Pd(dba)2 9.8mg、X-Phos 16mg、磷酸三鉀 135mg，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於TFA 1.0mL中，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲酸。Example 175 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-Methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer -B synthesis (step 1) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl) obtained in step 1 of Example 41 Yl-1,3,2-dioxaborolan-2-yl)benzoate 90mg, 5-bromo-6,7-difluoro-1-methyl-benzotriazole 68.6mg dissolved in 1,4-dioxane in 0.71 mL. At room temperature, 9.8 mg of Pd(dba) 2 , 16 mg of X-Phos, and 135 mg of tripotassium phosphate were added, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 1.0 mL of TFA, and stirred at room temperature for 2 hours. MTBE was added, washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1) -Methyl-benzotriazol-5-yl)benzoic acid.

(步驟2)將前述步驟1所得到的3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲酸 30mg、實施例155之步驟3所得到的N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 30.6mg溶解於THF 0.367mL中。於室溫添加TEA 0.042mL、HATU 55.9mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1R,3S,4S)-rel-7-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 2) The 3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl) obtained in the aforementioned step 1 ) 30 mg of benzoic acid, N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-di obtained in step 3 of Example 155 30.6 mg of nitrobenzenesulfonamide-isomer-B hydrochloride was dissolved in 0.367 mL of THF. 0.042 mL of TEA and 55.9 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1R,3S,4S)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-7-azabicyclo[2.2. 1] Heptan-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

(步驟3)將前述步驟2所得到的N-[(1R,3S,4S)-rel-7-[3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 51mg溶解於DCM 0.70mL中。於0℃下添加巰基乙酸 5.8μL、TEA 29.1μL，於室溫攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1R,3S,4S)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7- Difluoro-1-methyl-benzotriazol-5-yl)benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonate 51 mg of Amide-Isomer-B was dissolved in 0.70 mL of DCM. Add 5.8 μL of thioglycolic acid and 29.1 μL of TEA at 0°C, and stir at room temperature for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例176　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈-異構物-B之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 2.3g、實施例142之步驟1所得到的1-(5-溴-6-氟-1H-吲唑-1-基)-2-甲基丙烷-2-醇 2.03g溶解於1,4-二噁烷18.7mL中。於室溫下添加Pd(dba)2 250mg、X-Phos 414mg、磷酸三鉀 3.46g，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 10.0mL中。於0℃添加12當量濃度鹽酸 10.0mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲酸。Example 176 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Synthesis of fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B ( Step 1) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3) obtained in step 1 of Example 41 , 2-dioxoleborolan-2-yl) benzoate 2.3g, 1-(5-bromo-6-fluoro-1H-indazol-1-yl obtained in step 1 of Example 142 ) 2.03 g of 2-methylpropane-2-ol was dissolved in 18.7 mL of 1,4-dioxane. Pd(dba) 2 250 mg, X-Phos 414 mg, and 3.46 g of tripotassium phosphate were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 10.0 mL of THF. 10.0 mL of 12 equivalents of hydrochloric acid was added at 0°C, and stirred at room temperature for 2 hours. MTBE was added, washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2 -Hydroxy-2-methyl-propyl)indazol-5-yl]benzoic acid.

(步驟2)將前述步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲酸 30mg、實施例155之步驟3所得到的N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 27.9mg溶解於THF 0.34mL中。於室溫添加TEA 0.038mL、HATU 51.0mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 2) The 3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-(2-hydroxy-2-methyl-propyl)indole obtained in the aforementioned step 1 Azol-5-yl]benzoic acid 30 mg, N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl) obtained in step 3 of Example 155 27.9 mg of 2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride was dissolved in 0.34 mL of THF. 0.038 mL of TEA and 51.0 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3R,4R)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzyl]-7-nitrogen Heterobicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

(步驟3)將前述步驟2所得到的N-[(1S,3R,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 45mg溶解於DCM 0.58mL中。於0℃下添加巰基乙酸 4.9μL、TEA 24μL，於室溫攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro- 1-(2-Hydroxy-2-methyl-propyl)indazol-5-yl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4- Dinitrobenzenesulfonamide-isomer-B 45 mg was dissolved in 0.58 mL of DCM. Add 4.9 μL of thioglycolic acid and 24 μL of TEA at 0°C, and stir at room temperature for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例177　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-B之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 3.2g、實施例161之步驟3所得到的1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇 3.01g溶解於1,4-二噁烷25.2mL中。於室溫下添加Pd(dba)2 348mg、X-Phos 577mg、磷酸三鉀 4.81g，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 15.0mL中。於0℃添加12當量濃度鹽酸 15.0mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸。Example 177 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-(2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile-isomer-B synthesis (step 1) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-( 4,4,5,5-tetramethyl-1,3,2-dioxole-2-yl)benzoate 3.2g, the 1-(5) obtained in step 3 of Example 161 3.01 g of -bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol was dissolved in 25.2 mL of 1,4-dioxane. Pd(dba) 2 348 mg, X-Phos 577 mg, and 4.81 g of tripotassium phosphate were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 15.0 mL of THF. 15.0 mL of 12 equivalents of hydrochloric acid was added at 0°C, and stirred at room temperature for 2 hours. Add MTBE, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1 -(2-Hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid.

(步驟2)將前述步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸 30mg、實施例155之步驟3所得到的N-((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽 26.8mg溶解於THF 0.33mL中。於室溫添加TEA 0.037mL、HATU 48.9mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,2S,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B。(Step 2) The 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propane) obtained in the aforementioned step 1 Yl)benzotriazol-5-yl]benzoic acid 30mg, N-((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptane obtained in step 3 of Example 155 26.8 mg of 2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride was dissolved in 0.33 mL of THF. 0.037 mL of TEA and 48.9 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,2S,4R)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl ]-7-Azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

(步驟3)將前述步驟2所得到的N-[(1S,2S,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺-異構物-B 43mg溶解於DCM 0.54mL中。於0℃下添加巰基乙酸 4.5μL、TEA 22.7μL，於室溫攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層之後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The N-[(1S,2S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7- Difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl] 43 mg of -2,4-dinitrobenzenesulfonamide-isomer-B was dissolved in 0.54 mL of DCM. Add 4.5 μL of thioglycolic acid and 22.7 μL of TEA at 0°C, and stir at room temperature for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and after drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例178　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(3-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)以實施例41(步驟1~4)為準，藉由使用實施例142(步驟1)所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到第三丁基　N-((3-內)-8-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯。Example 178 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(3-bromo-6-fluoro-1- Synthesis of (2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile (step 1) 41 (Steps 1 to 4) shall prevail, by using the 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propane-2 obtained in Example 142 (Step 1) -Alcohol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain tertiary butyl N-((3-internal)-8-(4' -Cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl] -3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-((3-內)-8-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯 10mg溶解於DMF 0.076mL中，添加NBS 3.5mg，於80℃徹夜攪拌。以1mL之DMSO稀釋反應液，並以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 2) The tertiary butyl N-((3-internal)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2- Hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]octane-3- 10 mg of carbamic acid ester was dissolved in 0.076 mL of DMF, 3.5 mg of NBS was added, and the mixture was stirred at 80°C overnight. The reaction solution was diluted with 1 mL of DMSO and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例179　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(5-氟-3-甲基苯并[d]異噁唑-6-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將3-溴-4-氟酚　5g溶解於二氯甲烷 114mL中，於0℃添加TEA 5.5mL，並藉由滴下以添加氯化乙醯2.8mL。於20℃攪拌反應液30分鐘，以二氯甲烷 100mL稀釋。以0.5當量濃度鹽酸、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨、蒸餾去除溶劑，藉此得到3-溴-4-氟苯基　乙酸酯。Example 179 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(5-fluoro-3- Synthesis of methylbenzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) Dissolve 5g of 3-bromo-4-fluorophenol in dichloromethane To 114 mL of methane, 5.5 mL of TEA was added at 0°C, and 2.8 mL of acetyl chloride was added by dropping. The reaction solution was stirred at 20°C for 30 minutes and diluted with 100 mL of dichloromethane. It was washed with 0.5 equivalent of hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, and the solvent was distilled off to obtain 3-bromo-4-fluorophenyl "acetate.

(步驟2)對前述步驟1所得到的3-溴-4-氟苯基　乙酸酯 6.2g添加三氟化硼-乙酸錯合物　53mL，於155℃攪拌14小時。將反應液冷卻至0℃，加入冰。濾取析出物，以0℃之水洗淨，進行乾燥。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化所得到的固體，藉此得到1-(4-溴-5-氟-2-羥基苯基)乙酮。(Step 2) To 6.2 g of 3-bromo-4-fluorophenyl "acetate" obtained in step 1 above, 53 mL of boron trifluoride-acetic acid complex was added, and the mixture was stirred at 155°C for 14 hours. The reaction solution was cooled to 0°C, and ice was added. The precipitate was filtered, washed with water at 0°C, and dried. The obtained solid was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethanone.

(步驟3)對前述步驟2所得到的1-(4-溴-5-氟-2-羥基苯基)乙酮　2.16g及羥基胺鹽酸鹽 1.29g、乙酸鈉 1.14g添加MeOH 30mL，於60℃攪拌1小時。將反應液加至冰水中，濾取析出物，以水洗淨並乾燥。將所得到的固體溶解於THF 31mL中，添加TEA 1.68mL、N,N’-羰基二咪唑 1.65g，於70℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/乙酸乙酯)純化殘渣，藉此得到6-溴-5-氟-3-甲基苯并[d]異噁唑。(Step 3) Add 30 mL of MeOH to 2.16 g of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethanone, 1.29 g of hydroxylamine hydrochloride and 1.14 g of sodium acetate obtained in step 2 above. Stir at 60°C for 1 hour. The reaction solution was added to ice water, and the precipitate was filtered, washed with water and dried. The obtained solid was dissolved in 31 mL of THF, 1.68 mL of TEA and 1.65 g of N,N'-carbonyldiimidazole were added, and the mixture was stirred at 70°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/ethyl acetate) to obtain 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole.

(步驟4)以實施例41(步驟1~5)為準，藉由使用前述步驟3所得到的6-溴-5-氟-3-甲基苯并[d]異噁唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 4) Based on Example 41 (Steps 1 to 5), the 1-bromo-5-fluoro-3-methylbenzo[d]isoxazole obtained in step 3 was used instead of 1- (4-Bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例180　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(5-氟-3-甲基苯并[d]異噁唑-6-基)-[1,1’-聯苯]-4-甲腈之合成以實施例37(步驟1~3)為準，藉由使用實施例179之步驟3所得到的6-溴-5-氟-3-甲基苯并[d]異噁唑來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 180 "(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-methylbenzo[d]isoxazole-6- Base)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 37 (steps 1 to 3), by using the 6-bromo-5-obtained in step 3 of Example 179 Fluoro-3-methylbenzo[d]isoxazole was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例181　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-3-甲基-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例178之步驟1所得到的第三丁基　N-((3-內)-8-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯 69mg溶解於DMF 0.53mL中，添加NBS 38mg，於80℃徹夜攪拌。冷卻至室溫，添加Boc2 O 200mg、DMAP 1mg，於室溫攪拌2小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((3-內)-8-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯。Example 181 5'-((3-Intra)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- The synthesis of (2-hydroxy-2-methylpropyl)-3-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (step 1) will be implemented The tertiary butyl N-((3-internal)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2) obtained in step 1 of Example 178 -Methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)amine 69 mg of formate was dissolved in 0.53 mL of DMF, 38 mg of NBS was added, and the mixture was stirred at 80°C overnight. After cooling to room temperature, 200 mg of Boc 2 O and 1 mg of DMAP were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added, washed with water and saturated brine in this order, and the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((3-intra)-8-(4'-cyano-3') -Fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)- 8-Azabicyclo[3.2.1]octan-3-yl)carbamate.

(步驟2)將前述步驟1所得到的第三丁基　((3-內)-8-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯 15mg、三甲基硼氧烴三聚物(trimethyl boroxine) 7.7mg、PdCl2 (dppf)CH2 Cl2 1mg、碳酸銫20mg懸浮於1,4-二噁烷中，在微波照射下於125℃攪拌30分鐘。蒸餾去除溶劑，對殘渣添加三氟乙酸0.2mL，於室溫添加攪拌10分鐘。以1mL之DMSO稀釋反應液，並以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 2) The tertiary butyl ((3-internal)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy- 2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl) Carbamate 15mg, trimethyl boroxine 7.7mg, PdCl 2 (dppf)CH 2 Cl 2 1mg, cesium carbonate 20mg suspended in 1,4-dioxane, irradiated in microwave Stir at 125°C for 30 minutes. The solvent was distilled off, 0.2 mL of trifluoroacetic acid was added to the residue, and the mixture was added and stirred at room temperature for 10 minutes. The reaction solution was diluted with 1 mL of DMSO and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例182　5’-((1R,2S,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成(步驟1)、將第三丁基　(1S,3S,4R)-rel-3-胺基-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯 919mg溶解於THF 14.4mL中。於0℃添加TEA 1.81mL、2,4-二硝基苯磺醯氯 1.73g，於室溫徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　(1S,3S,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯。Example 182``5'-((1R,2S,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'',3-difluoro-4 ''-(2-Hydroxy-2-methylpropyl)-[1,1':2',1''-terphenyl]-4-carbonitrile synthesis (step 1), the third butyl 919 mg of (1S,3S,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate was dissolved in 14.4 mL of THF. 1.81 mL of TEA and 1.73 g of 2,4-dinitrobenzenesulfonyl chloride were added at 0°C, and the mixture was stirred at room temperature overnight. Ethyl acetate was added, washed with water and saturated brine in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl(1S,3S,4R)-rel-3-[(2,4-dinitrobenzene) Yl)sulfonamido]-7-azabicyclo[2.2.1]heptane-7-carboxylate.

(步驟2)將前述步驟1所得到的第三丁基　(1S,3S,4R)-rel-3-[(2,4-二硝基苯基)磺醯胺基]-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯 100mg溶解於乙酸乙酯 1.00mL中。於室溫添加4當量濃度鹽酸-乙酸乙酯溶液 2.00mL，並於室溫攪拌1小時。減壓濃縮反應液，藉此得到N-[(1S,3S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺鹽酸鹽。(Step 2) The tertiary butyl (1S,3S,4R)-rel-3-[(2,4-dinitrophenyl)sulfonamido)-7-azabicyclo [2.2.1] 100 mg of heptane-7-carboxylate was dissolved in 1.00 mL of ethyl acetate. Add 2.00 mL of 4 equivalent hydrochloric acid-ethyl acetate solution at room temperature, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain N-[(1S,3S,4R)-rel-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzenesulfonate Amine hydrochloride.

(步驟3)將實施例166步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸 30mg、前述步驟2所得到的N-[(1S,3S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺鹽酸鹽 30.7mg溶解於THF 0.40mL中。於室溫添加TEA 0.0420mL、HATU 56.0mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到N-[(1S,3S,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺。(Step 3) The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl) obtained in step 2 of Example 166 )Phenyl]benzoic acid 30mg, N-[(1S,3S,4R)-rel-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-di obtained in step 2 above 30.7 mg of nitrobenzenesulfonamide hydrochloride was dissolved in 0.40 mL of THF. 0.0420 mL of TEA and 56.0 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain N-[(1S,3S,4R)-rel-7-[3-(4 -Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzyl]-7-azabicyclo[2.2 .1]Heptan-3-yl]-2,4-dinitrobenzenesulfonamide.

(步驟4)將前述步驟3所得到的N-[(1S,3S,4R)-rel-7-[3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲醯基]-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺 55mg溶解於DCM 0.752mL中。於0℃下添加巰基乙酸 6.27μL、TEA 31.4μL，於室溫攪拌2小時。添加氯仿，以4當量濃度氫氧化鈉水溶液洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The N-[(1S,3S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(2-fluoro- 4-(2-Hydroxy-2-methyl-propyl)phenyl]benzyl]-7-azabicyclo[2.2.1]heptan-3-yl]-2,4-dinitrobenzene 55 mg of sulfonamide was dissolved in 0.752 mL of DCM. Add 6.27 μL of thioglycolic acid and 31.4 μL of TEA at 0°C, and stir at room temperature for 2 hours. Chloroform was added, washed with 4 equivalents of sodium hydroxide aqueous solution, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例183　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例172步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸 30mg、第三丁基　N-[(3-內)-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 16.1mg溶解於THF 0.323mL中。於室溫添加TEA 0.027mL、HATU 49.1mg，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯。Example 183 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-( Synthesis of 2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile (Step 1) Example 172 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indole-5 obtained in step 2 30 mg of -yl]benzoic acid and 16.1 mg of tertiary butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate were dissolved in 0.323 mL of THF. 0.027 mL of TEA and 49.1 mg of HATU were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3-内)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]-8-azabicyclo[ 3.2.1] Octan-3-yl] carbamate.

(步驟2)將前述步驟1所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯 42mg溶解於MeOH 0.84mL中。於室溫添加4當量濃度鹽酸-1,4-二噁烷溶液 0.84mL，於室溫攪拌1小時。添加氯仿、2當量濃度氫氧化鈉水溶液 1.68mL、以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7- Difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate 42 mg of the acid ester was dissolved in MeOH 0.84 mL. Add 0.84 mL of 4 equivalents of hydrochloric acid-1,4-dioxane solution at room temperature, and stir at room temperature for 1 hour. Add chloroform and 1.68 mL of 2N sodium hydroxide aqueous solution, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例184　5’-((1R,2S,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例171(步驟1~3)為準，藉由使用實施例182步驟2所得到的N-[(1R,2S,4S)-rel-7-氮雜雙環[2.2.1]庚烷-3-基]-2,4-二硝基苯磺醯胺鹽酸鹽來代替N-((1R,2R,4S)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)-2,4-二硝基苯磺醯胺-異構物-B鹽酸鹽，而得到標題化合物。Example 184 "5'-((1R,2S,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 171 (Step 1 ~3) shall prevail, by using the N-[(1R,2S,4S)-rel-7-azabicyclo[2.2.1]heptan-3-yl]-2 obtained in step 2 of Example 182, 4-Dinitrobenzenesulfonamide hydrochloride instead of N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]heptan-2-yl)-2,4-di Nitrobenzenesulfonamide-isomer-B hydrochloride to obtain the title compound.

實施例185　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟3~4)為準，藉由使用實施例175步驟1所得到的3-(4-氰基-3-氟-苯基)-4-(6,7-二氟-1-甲基-苯并三唑-5-基)苯甲酸來代替3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸，且使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 185 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro Synthesis of -1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile for implementation Example 172 (Steps 3~4) shall prevail, by using the 3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-) obtained in step 1 of Example 175 Methyl-benzotriazol-5-yl)benzoic acid instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2 -Methyl-propyl)indol-5-yl]benzoic acid, and tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl is used ) Carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl] carbamate to obtain the title compound.

實施例186　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-7-甲氧基-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成　(步驟1)將5-溴-2,3,4-三氟-苯甲醛480mg溶解於1,2-二甲氧乙烷 4.8mL中。於室溫添加肼一水合物　7.68mL，於80℃攪拌5小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到5-溴-6,7-二氟-1H-吲唑。Example 186 "5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- Synthesis of (2-hydroxy-2-methylpropyl)-7-methoxy-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (step 1) 480 mg of 5-bromo-2,3,4-trifluoro-benzaldehyde was dissolved in 4.8 mL of 1,2-dimethoxyethane. At room temperature, 7.68 mL of hydrazine monohydrate was added, and the mixture was stirred at 80°C for 5 hours. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 5-bromo-6,7-difluoro-1H-indazole.

(步驟2)將前述步驟1所得到的5-溴-6,7-二氟-1H-吲唑　97mg溶解於DMF 1.38mL中。於室溫添加甲醇0.1mL、碳酸銫　271mg、2,2-二甲基環氧乙烷 0.074mL，於80℃攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-7-甲氧基-吲唑-1-基)-2-甲基-丙烷-2-醇。(Step 2) Dissolve 97 mg of 5-bromo-6,7-difluoro-1H-indazole obtained in Step 1 above in 1.38 mL of DMF. 0.1 mL of methanol, 271 mg of cesium carbonate, and 0.074 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 80°C for 1 hour. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-7-methoxy-indazol-1-yl)-2 -Methyl-propan-2-ol.

(步驟3)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 45.0mg、前述步驟2所得到的、1-(5-溴-6-氟-7-甲氧基-吲唑-1-基)-2-甲基-丙烷-2-醇 43.8mg溶解於1,4-二噁烷0.50mL中。於室溫下，添加Pd(dba)2 4.89mg、X-Phos 8.11mg、磷酸三鉀 67.7mg，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 0.45mL中。於0℃添加12當量濃度鹽酸 0.56mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)-7-甲氧基-吲唑-5-基]苯甲酸。(Step 3) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1, 3,2-Dioxolpan-2-yl)benzoate 45.0mg, obtained in step 2 above, 1-(5-bromo-6-fluoro-7-methoxy-indazole- 43.8 mg of 1-yl)-2-methyl-propan-2-ol was dissolved in 0.50 mL of 1,4-dioxane. At room temperature, 4.89 mg of Pd(dba) 2, 8.11 mg of X-Phos, and 67.7 mg of tripotassium phosphate were added, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 0.45 mL of THF. 0.56 mL of 12 equivalents of hydrochloric acid was added at 0°C, and stirred at room temperature for 2 hours. Add MTBE, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2- Hydroxy-2-methyl-propyl)-7-methoxy-indazol-5-yl]benzoic acid.

(步驟4)以實施例172(步驟3~4)為準，藉由使用前述步驟3所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)-7-甲氧基-吲唑-5-基]苯甲酸來代替3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸，且使用第三丁基　((3-內)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。(Step 4) Based on Example 172 (Steps 3~4), by using the 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1 obtained in step 3 above -(2-Hydroxy-2-methyl-propyl)-7-methoxy-indazol-5-yl)benzoic acid instead of 3-(4-cyano-3-fluoro-phenyl)-4- [6,7-Difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid and tertiary butyl((3-endo)-8-aza Bicyclo[3.2.1]octan-3-yl)carbamate was substituted for tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例187　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例186之步驟1所得到的5-溴-6,7-二氟-1H-吲唑　101mg溶解於DMF 1.44mL中。於室溫添加碳酸銫　283mg、2,2-二甲基環氧乙烷 0.077mL，於80℃徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6,7-二氟-吲唑-1-基)-2-甲基-丙烷-2-醇。(步驟2)以實施例172(步驟2~4)為準，藉由使用前述步驟1所得到的1-(5-溴-6,7-二氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 187 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H -Indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) The 5-bromo-6,7 obtained in step 1 of Example 186 -101 mg of difluoro-1H-indazole was dissolved in 1.44 mL of DMF. 283 mg of cesium carbonate and 0.077 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 80°C overnight. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2-methyl -Propane-2-ol. (Step 2) Based on Example 172 (Steps 2~4), by using the 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2- Methyl-propane-2-ol was substituted for 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol to obtain the title compound.

實施例188　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例187步驟1所得到的1-(5-溴-6,7-二氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　((3-內)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 188 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-( 2-Hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Step 2~ 4) shall prevail, by using the 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in step 1 of Example 187 instead 1-(5-Bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the use of tertiary butyl ((3-into)-8-aza Bicyclo[3.2.1]octan-3-yl)carbamate was substituted for tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例189　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例142步驟1所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 189 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Step 2 ~4) shall prevail, by using 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in step 1 of Example 142 instead of 1- (5-Bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the use of tertiary butyl ((1S,2S,4R)-rel-7- Azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, and get the title Compound.

實施例190　(S)-5’-(3-胺基-3-甲基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例136步驟1所得到的1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　(S)-(3-甲基吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 190 (S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methyl The synthesis of propyl group)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (Steps 2~4), by using Example 136 The 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol obtained in step 1 replaces the 1-(5-bromo-6,7-difluoro- Indol-1-yl)-2-methyl-propan-2-ol, and tertiary butyl (S)-(3-methylpyrrolidin-3-yl) carbamate is used instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例191　(S)-5’-(3-胺基-3-甲基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟3~4)為準，藉由使用實施例177步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸來代替3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸，且使用第三丁基　(S)-(3-甲基吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 191 ``(S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) Propyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Steps 3~4) shall prevail, by using the 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2) obtained in step 1 of Example 177 -Hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro- 1-(2-Hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and tertiary butyl(S)-(3-methylpyrrolidin-3-yl)carbamic acid is used The ester replaces the tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例192　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟3~4)為準，藉由使用實施例177步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸來代替3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸，且使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 192 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-(2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile was synthesized in accordance with Example 172 (steps 3~4), by using the 3-(4-cyano-3-fluoro-phenyl)-4-obtained in step 1 of Example 177 [6,7-Difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid instead of 3-(4-cyano-3-fluoro-phenyl )-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and tertiary butyl ((1S,2S,4R )-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate Acid ester to obtain the title compound.

實施例193　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’’,3-二氟-4’’-(2-羥基-2-甲基丙基)-[1,1’:2’,1’’-聯三苯]-4-甲腈之合成以實施例172(步驟3~4)為準，藉由使用實施例166步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯甲酸來代替3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸，且使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 193 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'',3-difluoro-4 The synthesis of''-(2-hydroxy-2-methylpropyl)-[1,1':2',1''-terphenyl]-4-carbonitrile is based on Example 172 (Steps 3~4) As standard, by using the 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propane) obtained in step 2 of Example 166 Yl)phenyl]benzoic acid instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl) Indol-5-yl]benzoic acid and tertiary butyl((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride The salt replaces the tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例194　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(3-羥基-3-甲基丁基)-1H-吲唑-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6-氟-1H-吲唑　200mg溶解於DMF 3.1mL中。於室溫添加碳酸銫　606mg、(3-羥基-3-甲基-丁基) 4-甲基苯磺酸 481mg，於90℃攪拌16小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-(5-溴-6-氟-吲唑-1-基)-2-甲基-丁烷-2-醇。Example 194 "5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- Synthesis of (3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile (Step 1) The 5-bromo-6- 200 mg of fluoro-1H-indazole was dissolved in 3.1 mL of DMF. 606 mg of cesium carbonate and 481 mg of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonic acid were added at room temperature, and the mixture was stirred at 90°C for 16 hours. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-butane -2-ol.

(步驟2)以實施例172(步驟2~4)為準，藉由使用前述步驟1所得到的4-(5-溴-6-氟-吲唑-1-基)-2-甲基-丁烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　((3-內)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。(Step 2) Based on Example 172 (Steps 2 to 4), by using the 4-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl- Butane-2-ol instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the tertiary butyl ((3 -Ino)-8-azabicyclo[3.2.1]octan-3-yl)carbamate instead of tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate, The title compound is obtained.

實施例195　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例187步驟1所得到的1-(5-溴-6,7-二氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 195 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-(2-Hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Steps 2~4) shall prevail, by using the 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2-methyl-propane-2 obtained in step 1 of Example 187 -Alcohol instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the use of tertiary butyl ((1S,2S,4R )-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate Acid ester to obtain the title compound.

實施例196　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟1~4)為準，藉由使用第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 196 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-(2-Hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Steps 1~4) shall prevail, by using tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride The salt replaces the tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例197　(S)-5’-(3-胺基-3-甲基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例187步驟1所得到的1-(5-溴-6,7-二氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　(S)-(3-甲基吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 197 ``(S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) The synthesis of propyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (steps 2~4), by using The 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2-methyl-propane-2-ol obtained in step 1 of Example 187 replaced 1-(5-bromo-6 ,7-Difluoro-indol-1-yl)-2-methyl-propan-2-ol, and tertiary butyl(S)-(3-methylpyrrolidin-3-yl)carbamic acid The ester replaces the tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound.

實施例198　(S)-5’-(3-胺基-3-甲基吡咯啶-1-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟1~4)為準，藉由使用第三丁基　(S)-(3-甲基吡咯啶-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 198 ``(S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) The synthesis of propyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (steps 1 to 4), by using Tertiary butyl (S)-(3-methylpyrrolidin-3-yl) carbamate replaces tertiary butyl N-[(3S)-pyrrolidin-3-yl] carbamate, and The title compound is obtained.

實施例199　3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-5’-(2,7-二氮雜螺[3.4]辛烷-6-羰基)-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例142步驟1所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　2,7-二氮雜螺[3.4]辛烷-2-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 199 ``3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-5'-(2,7-diazepine The synthesis of heterospiro[3.4]octane-6-carbonyl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (Steps 2~4), by using Example 142 Step 1 The resulting 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol replaces 1-(5-bromo-6,7-difluoro-indole -1-yl)-2-methyl-propan-2-ol, and use tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N- [(3S)-pyrrolidin-3-yl] carbamate to obtain the title compound.

實施例200　2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-5’-(2,7-二氮雜螺[3.4]辛烷-6-羰基)-[1,1’-聯苯]-4-甲腈之合成　以實施例172(步驟1~4)為準，藉由使用第三丁基　2,7-二氮雜螺[3.4]辛烷-2-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 200 ``2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'-(2,7 -Diazaspiro[3.4]octane-6-carbonyl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in accordance with Example 172 (steps 1 to 4), by using the third Butyl 2,7-diazaspiro[3.4]octane-2-carboxylate replaces tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound .

實施例201　2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-5’-(2,8-二氮雜螺[3.5]壬烷-2-羰基)-[1,1’-聯苯]-4-甲腈之合成　以實施例172(步驟1~4)為準，藉由使用第三丁基　2,8-二氮雜螺[3.5]壬烷-6-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 201 ``2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'-(2,8 The synthesis of -diazaspiro[3.5]nonane-2-carbonyl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (steps 1 to 4), by using the third Butyl 2,8-diazaspiro[3.5]nonane-6-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title compound .

實施例202　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(5-氟-3-甲基苯并[d]異噁唑-6-基)-[1,1’-聯苯]-4-甲腈-異構物-X之合成(步驟1)將第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽 36mg溶解於DCM 2.89mL中。於室溫添加TEA 40μL、氯甲酸苯甲酯 25μL，並於室溫攪拌1小時。蒸餾去除溶劑，添加氯仿、水，以氯仿萃取2次，以水、飽和食鹽水洗淨。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯。Example 202 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(5- Synthesis of fluoro-3-methylbenzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-X (Step 1) 36 mg of yl((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate hydrochloride was dissolved in 2.89mL of DCM. Add 40 μL of TEA and 25 μL of benzyl chloroformate at room temperature, and stir at room temperature for 1 hour. The solvent was distilled off, chloroform and water were added, extracted with chloroform twice, and washed with water and saturated brine. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain benzyl (1S, 2S, 4R)-rel-2-((tertiary butoxy) Carbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.

將苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯作成10mg/mL之乙醇溶液，並藉以下條件分離。The benzyl (1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate was made 10mg/ mL of ethanol solution, and separated by the following conditions.

將保持時間快者定義為異構物-X，保持時間慢著定義為異構物-Y。管柱：DAICEL　CHIRALPAK　IC　2.0　×25　cm移動相：己烷/2-丙醇＝85/15流速：12.5mL/min各異構物之保持時間：苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-X： 16.93分苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-Y： 23.82分。The one with fast retention time is defined as isomer-X, and the one with slow retention time is defined as isomer-Y. Column: DAICEL　CHIRALPAK　IC　2.0　×25　cm Mobile phase: hexane/2-propanol=85/15 Flow rate: 12.5mL/min Retention time of each isomer: benzyl (1S, 2S, 4R)-rel -2-((Third-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-X: 16.93 points benzyl (1S, 2S ,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-Y: 23.82 points.

掌性分析條件管柱：CHIRALPAK　IC　4.6x150　mm移動相：己烷/2-丙醇＝85/15流速：1.0mL/min各異構物之保持時間：苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-X： 6.972分苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-Y： 9.895分。Palm analysis conditions. Column: CHIRALPAK　IC　4.6x150　mm Mobile phase: hexane/2-propanol=85/15 Flow rate: 1.0mL/min Retention time of each isomer: benzyl (1S, 2S, 4R) -rel-2-((Third-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-X: 6.972 points benzyl (1S ,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-Y: 9.895 points .

(步驟2)將前述步驟1所得到的苯甲基　(1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羧酸酯-異構物-X 93g、10%Pd/C 10g懸浮於甲醇1.0L中。50psi之氫環境氣體下，於室溫攪拌5小時。過濾反應液、濃縮濾液，藉此得到第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(步驟3)以實施例172(步驟2~4)為準，藉由使用實施例179步驟3所得到的6-溴-5-氟-3-甲基苯并[d]異噁唑來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。(Step 2) The benzyl (1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptan obtained in the previous step 1 Alkyl-7-carboxylate-isomer-X 93g, 10% Pd/C 10g suspended in 1.0L methanol. Under 50psi hydrogen atmosphere, stir at room temperature for 5 hours. The reaction liquid was filtered and the filtrate was concentrated to obtain tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer -X. (Step 3) Take Example 172 (Steps 2~4) as the standard, by using the 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole obtained in Step 3 of Example 179 instead 1-(5-Bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the tertiary butyl ((1S,2S ,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X instead of tert-butyl N-[(3S)-pyrrolidine-3 -Yl] carbamate to obtain the title compound.

實施例203　2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-3-氟-5’-(八氫吡咯并[3,4-c]吡咯-2-羰基)-[1,1’-聯苯]-4-甲腈之合成　以實施例172(步驟1~4)為準，藉由使用第三丁基　六氫吡咯并[3,4-c]吡咯-2(1H)-羧酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。實施例204　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6-氟-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將5-溴-6-氟-1H-吲唑 300mg溶解於DMF 4.65mL中。於室溫添加碳酸銫 90.9mg、2,2-二乙基環氧乙烷 0.20mL，於90℃攪拌16小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇。Example 203 　 2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'-(octahydropyrrole The synthesis of and [3,4-c]pyrrole-2-carbonyl)-[1,1'-biphenyl]-4-carbonitrile is based on Example 172 (steps 1 to 4), by using tertiary Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to obtain the title Compound. Example 204 (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-indazole Synthesis of -5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile (Step 1) Dissolve 300 mg of 5-bromo-6-fluoro-1H-indazole in 4.65 mL of DMF . 90.9 mg of cesium carbonate and 0.20 mL of 2,2-diethyloxirane were added at room temperature, and the mixture was stirred at 90°C for 16 hours. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentane-3 -alcohol.

(步驟2)以實施例172(步驟2~4)為準，藉由使用前述步驟1所得到的3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 172 (Steps 2 to 4), by using the 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentane obtained in step 1 above -3-ol instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol to obtain the title compound.

實施例205　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6-氟-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例172(步驟2~4)為準，藉由使用實施例204步驟1所得到的3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用第三丁基　((3-內)-8-氮雜雙環[3.2.1]辛烷-3-基)胺甲酸酯來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 205 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(2-ethyl-2- (Hydroxybutyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 172 (Steps 2~4) Standard, by using the 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentane-3-ol obtained in step 1 of Example 204 instead of 1-(5-bromo- 6,7-Difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the use of tertiary butyl ((3-endo)-8-azabicyclo[3.2.1]octane Alk-3-yl) carbamate replaces the tertiary butyl N-[(3S)-pyrrolidin-3-yl] carbamate to obtain the title compound.

實施例206　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6-氟-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例172(步驟2~4)為準，藉由使用實施例204步驟1所得到的3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇來代替1-(5-溴-6,7-二氟-吲哚-1-基)-2-甲基-丙烷-2-醇，且使用實施例202步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X來代替第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯，而得到標題化合物。Example 206 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethane 2-hydroxybutyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X synthesis Example 172 (steps 2 to 4) is the standard, by using the 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentane-3- Alcohol instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and the tertiary butyl group obtained in step 2 of Example 202 was used ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X instead of tertiary butyl N-[(3S) -Pyrrolidin-3-yl] carbamate to obtain the title compound.

實施例207　2-(5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸 -異構物-X之合成(步驟1)將5-溴-6-氟-1H-吲哚　500mg溶解於DMF 7.79mL中。於室溫添加碳酸銫 1.67g、乙基　2-氯乙酸酯 573mg，於90℃攪拌16小時。以飽和氯化銨水溶液停止反應。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到乙基　2-(5-溴-6-氟-吲哚-1-基)乙酸酯。Example 207 ``2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano -3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid-isomer-X synthesis (step 1) 500 mg of bromo-6-fluoro-1H-indole was dissolved in 7.79 mL of DMF. 1.67 g of cesium carbonate and 573 mg of ethyl "2-chloroacetate" were added at room temperature, and the mixture was stirred at 90°C for 16 hours. The reaction was stopped with saturated aqueous ammonium chloride solution. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain ethyl 2-(5-bromo-6-fluoro-indol-1-yl) acetate.

(步驟2)將實施例41步驟2所得到的3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸 2g、實施例202步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 1.24g溶解於THF 21.8mL中。於室溫添加TEA 1.52mL、HATU 2.28g，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(Step 2) The 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxolane-2-yl)benzoic acid 2g, the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan obtained in step 2 of Example 202 Alk-2-yl) carbamate-isomer-X 1.24 g was dissolved in 21.8 mL of THF. TEA 1.52mL and HATU 2.28g were added at room temperature, and stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S, 2S, 4R)-rel-7-(4' -Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-linked Benzene]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X.

(步驟3)將前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 100mg、前述步驟1所得到的乙基　2-(5-溴-6-氟-吲哚-1-基)乙酸酯 69.5mg懸浮於1,4-二噁烷0.59mL中。於室溫添加Pd(dba)2 8.2mg、X-phos 13.6mg、磷酸三鉀 113mg，進行脫氣、氮取代。在氮環境氣體下，於外溫100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣。將殘渣溶解於MeOH 1.0mL中，添加5當量濃度氫氧化鈉水溶液 1.0mL，攪拌1小時。添加MTBE，於水層萃取。以鹽酸使水層成為酸性，添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑，藉此得到2-(5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸 -異構物-X。(Step 3) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5) obtained in the aforementioned step 2 -Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan Alk-2-yl) carbamate-isomer-X 100mg, 69.5mg of ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate obtained in step 1 above, suspended In 1,4-dioxane 0.59mL. Add 8.2 mg of Pd(dba)2, 13.6 mg of X-phos, and 113 mg of tripotassium phosphate at room temperature for degassing and nitrogen substitution. Under a nitrogen atmosphere, stir overnight at an external temperature of 100°C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in 1.0 mL of MeOH, 1.0 mL of a 5-N sodium hydroxide aqueous solution was added, and the mixture was stirred for 1 hour. Add MTBE and extract in the water layer. Make the water layer acidic with hydrochloric acid, add MTBE, wash sequentially with water and saturated brine, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent to obtain 2-(5-(5-((1S,2S ,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro- [1,1'-Biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid-isomer-X.

(步驟4)對前述步驟3所得到的2-(5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸 -異構物-X 10mg添加乙腈 1.0mL、4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL，攪拌30分鐘。蒸餾去除溶劑，以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) For the 2-(5-(5-((1S,2S,4R)-rel-2-((3rd butoxycarbonyl)amino)-7-azabicyclo [2.2.1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indole-1- Add 1.0 mL of acetonitrile and 1.0 mL of 4-eq hydrochloric acid-1,4-dioxane solution to 10 mg of acetic acid-isomer-X, and stir for 30 minutes. The solvent was distilled off, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例208　2-(4’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’’-氰基-2,3’’-二氟-[1,1’:2’,1’’-聯三苯]-4-基)乙酸 -異構物-X之合成以實施例207(步驟3~4)為準，藉由使用甲基　2-(4-溴-3-氟苯基)乙酸酯來代替乙基　2-(5-溴-6-氟-吲哚-1-基)乙酸酯，而得到標題化合物。Example 208 ``2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4''-cyano- The synthesis of 2,3''-difluoro-[1,1':2',1''-terphenyl]-4-yl)acetic acid-isomer-X is in Example 207 (Steps 3~4) As standard, by using methyl 2-(4-bromo-3-fluorophenyl)acetate instead of ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate, The title compound is obtained.

實施例209　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成(步驟1)將2-氯-1,3-二氟-4-硝基-苯 1g溶解於THF 12.9mL中並添加TEA 1.08mL、1-胺基-2-甲基-丙烷-2-醇 0.59mL，於室溫攪拌1小時。添加乙酸乙酯，並以水、飽和食鹽水依序洗淨。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑，藉此得到1-(2-氯-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。Example 209 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked Synthesis of benzene]-4-carbonitrile-isomer-X (Step 1) Dissolve 1g of 2-chloro-1,3-difluoro-4-nitro-benzene in 12.9mL of THF and add 1.08mL of TEA, 0.59 mL of 1-amino-2-methyl-propan-2-ol was stirred at room temperature for 1 hour. Add ethyl acetate, and wash with water and saturated saline in this order. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off to obtain 1-(2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

(步驟2)將前述步驟1所得到的1-(2-氯-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.3g溶解於DMF 9.9mL中。於室溫添加NBS 1.1g，並於90℃攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以IPE：己烷＝1：1進行結晶化，並以己烷洗淨2次，藉此得到1-(4-溴-2-氯-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。(Step 2) Dissolve 1.3 g of 1-(2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 1 above in 9.9 mL of DMF. 1.1 g of NBS was added at room temperature, and stirred at 90°C for 1 hour. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. Crystallize with IPE:hexane=1:1 and wash with hexane twice to obtain 1-(4-bromo-2-chloro-3-fluoro-6-nitro-anilino)-2 -Methyl-propan-2-ol.

(步驟3)將前述步驟2所得到的1-(4-溴-2-氯-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.6g及NH4 Cl　1.6g、鐵0.8g懸浮於EtOH 7.81mL、水 7.81mL中，並於60℃徹夜攪拌。添加MTBE，進行矽藻土過濾。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑，藉此得到1-(6-胺基-4-溴-2-氯-3-氟-苯胺基)-2-甲基-丙烷-2-醇。(Step 3) Combine 1.6 g of 1-(4-bromo-2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 2 above and NH 4 1.6 g of Cl and 0.8 g of iron were suspended in 7.81 mL of EtOH and 7.81 mL of water, and stirred overnight at 60°C. Add MTBE and filter with diatomaceous earth. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 1-(6-amino-4-bromo-2-chloro-3-fluoro-anilino) -2-Methyl-propan-2-ol.

(步驟4)將前述步驟3所得到的1-(6-胺基-4-溴-2-氯-3-氟-苯胺基)-2-甲基-丙烷-2-醇 352mg、溶解於水0.70mL、THF 1.76mL中。於0℃添加12當量濃度鹽酸1.06mL，滴下添加亞硝酸鈉(使101mg溶解而成的水溶液0.3mL)，於室溫攪拌1小時。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。對殘渣添加IPE：己烷＝1：1 68mL，並濾取，且以IPE：己烷＝1：1洗淨，藉此得到1-(5-溴-7-氯-6-氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇。(Step 4) 352 mg of 1-(6-amino-4-bromo-2-chloro-3-fluoro-anilino)-2-methyl-propan-2-ol obtained in step 3 above was dissolved in water 0.70mL, THF 1.76mL. 1.06 mL of 12 equivalents of hydrochloric acid was added at 0°C, sodium nitrite (0.3 mL of an aqueous solution obtained by dissolving 101 mg) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. To the residue, 68 mL of IPE:hexane=1:1 was added, filtered, and washed with IPE:hexane=1:1 to obtain 1-(5-bromo-7-chloro-6-fluoro-benzo Triazol-1-yl)-2-methyl-propan-2-ol.

(步驟5)將實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 50mg、前述步驟4所得到的1-(5-溴-7-氯-6-氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇 37.4mg懸浮於1,4-二噁烷0.3mL中。於室溫添加Pd(dba)2 4.1mg、X-phos 6.8mg、磷酸三鉀56.7mg，並進行氮取代，於100℃攪拌2小時。添加乙酸乙酯，裝入NH矽膠中，並以乙酸乙酯：甲醇＝10：1洗淨。蒸餾去除溶劑，對殘渣添加乙腈 1.0mL、4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL並攪拌10分鐘。蒸餾去除溶劑，將殘渣溶解於DMSO中，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 5) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5) obtained in step 2 of Example 207 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X 50mg, 1-(5-bromo-7-chloro-6-fluoro-benzotriazol-1-yl) obtained in step 4 above 37.4 mg of -2-methyl-propan-2-ol was suspended in 0.3 mL of 1,4-dioxane. Pd(dba) 2 4.1 mg, X-phos 6.8 mg, and tripotassium phosphate 56.7 mg were added at room temperature, followed by nitrogen substitution, and stirred at 100°C for 2 hours. Add ethyl acetate, put it into NH silica gel, and wash with ethyl acetate: methanol = 10:1. The solvent was distilled off, 1.0 mL of acetonitrile and 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 10 minutes. The solvent was distilled off, the residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例210　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-氯-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈　之合成以實施例209(步驟1~5)為準，藉由使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 210 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)- The synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was carried out in Example 209 (Step 1~ 5) shall prevail, by using the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl Group ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer -X to obtain the title compound.

實施例211　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-氯-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 211 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-6-fluoro-1- (2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4 -The synthesis of formonitrile is based on Example 209 (Steps 1 to 5), by using the tertiary butyl N-[(3-内)-8-[3-(4- Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)- 8-azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'- Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl) -7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例212　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-3-羧酸-異構物-X之合成(步驟1)將實施例176步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲唑-5-基]苯甲酸 250mg溶解於THF 2.24mL中。於室溫添加HATU 234mg、實施例202步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 125mg、TEA 0.156mL，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。Example 212 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid-isomer -X synthesis (step 1) The 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl) obtained in step 1 of Example 176 250 mg of propyl-propyl)indazol-5-yl]benzoic acid was dissolved in 2.24 mL of THF. Add 234 mg of HATU and the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamic acid obtained in step 2 of Example 202 at room temperature Ester-isomer-X 125 mg, TEA 0.156 mL, and stirring at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro- 6-(6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-nitrogen Heterobicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X.

(步驟2)將前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 289mg溶解於DMF 4.50mL中。於室溫添加NBS 120mg，並於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(6-(3-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-4’-氰基-3’-氟-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(Step 2) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-( 2-Hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptane- 2-yl) carbamate-isomer-X 289 mg was dissolved in 4.50 mL of DMF. 120 mg of NBS was added at room temperature, and stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(6-(3-bromo-6) -Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-3 -Carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X.

(步驟3)將前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(6-(3-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-4’-氰基-3’-氟-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 50mg、PdCl2 (PPh3 )2 2.4mg懸浮於1-甲基-2-吡咯啶酮 0.5mL中。於室溫添加N,N-二乙基乙醇胺 0.046mL，進行CO取代，於125℃攪拌1小時。於反應液中添加t-BuOH 0.5mL、2當量濃度氫氧化鈉水溶液 0.25mL，於室溫攪拌1小時。添加MTBE，分離水層。對水層添加鹽酸而使其成為酸性之後，以MTBE萃取。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。對殘渣添加乙腈 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL，攪拌10分鐘。濃縮反應液、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl ((1S,2S,4R)-rel-7-(6-(3-bromo-6-fluoro-1-(2-hydroxy-2-methyl) obtained in the aforementioned step 2 Propyl)-1H-indazol-5-yl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X 50 mg, PdCl 2 (PPh 3 ) 2 2.4 mg were suspended in 0.5 mL of 1-methyl-2-pyrrolidone. At room temperature, 0.046 mL of N,N-diethylethanolamine was added to perform CO substitution, and the mixture was stirred at 125°C for 1 hour. To the reaction solution, 0.5 mL of t-BuOH and 0.25 mL of a 2 equivalent sodium hydroxide aqueous solution were added, and the mixture was stirred at room temperature for 1 hour. Add MTBE and separate the water layer. After adding hydrochloric acid to the water layer to make it acidic, it was extracted with MTBE. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. To the residue, 0.5 mL of acetonitrile and 0.5 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added, and the mixture was stirred for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例213　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例41步驟2所得到的3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸 500mg、第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 鹽酸鹽 303.5mg溶解於THF 5.45mL中。於室溫添加TEA 0.379mL、HATU 569.5mg，於50℃攪拌1小時。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯。(步驟2)以實施例209(步驟1~5)為準，藉由使用前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 213 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked Synthesis of benzene)-4-carbonitrile (Step 1) The 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzoic acid 500mg, tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1] 303.5 mg of heptane-2-yl) carbamate hydrochloride was dissolved in 5.45 mL of THF. TEA 0.379 mL and HATU 569.5 mg were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S, 2S, 4R)-rel-7-(4' -Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-linked Benzene]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate. (Step 2) Based on Example 209 (Steps 1 to 5), by using the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano- 3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3 -Carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano -3'-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]- 3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例214　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X 之合成以實施例161(步驟1~5)為準，藉由使用3-[(2,3-二氟-6-硝基-苯胺基)甲基]戊烷-3-醇來代替1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇，且使用實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X來代替第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 214 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethane 2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile-isomer-X was synthesized in accordance with Example 161 (steps 1 to 5), by using 3-[(2,3-difluoro-6-nitro-anilino)methyl Yl]pentane-3-ol instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol, and use the one obtained in step 2 of Example 207 Tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate- Isomer -X instead of tertiary butyl N-[(3-internal)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate, The title compound is obtained.

實施例215　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例161(步驟1~5)為準，藉由使用3-[(2,3-二氟-6-硝基-苯胺基)甲基]戊烷-3-醇來代替1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇，且使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 215 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H -Benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized according to Example 161 (Steps 1~5 ) Shall prevail, by using 3-[(2,3-difluoro-6-nitro-anilino)methyl]pentane-3-ol instead of 1-(2,3-difluoro-6-nitro Yl-anilino)-2-methyl-propan-2-ol, and the tertiary butyl N-[(3S)-1-[3-(4-cyano-3 -Fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-3- Yl]carbamate instead of tertiary butyl N-[(3-internal)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate , And get the title compound.

實施例216　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例161(步驟1~5)為準，藉由使用3-[(2,3-二氟-6-硝基-苯胺基)甲基]戊烷-3-醇來代替1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇，而得到標題化合物。Example 216 "5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(2-ethyl-2- Hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- The synthesis of formonitrile is based on Example 161 (steps 1 to 5), and is replaced by 3-[(2,3-difluoro-6-nitro-anilino)methyl]pentane-3-ol 1-(2,3-Difluoro-6-nitro-anilino)-2-methyl-propan-2-ol to obtain the title compound.

實施例217　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例161(步驟1~5)為準，藉由使用3-[(2,3-二氟-6-硝基-苯胺基)甲基]戊烷-3-醇來代替1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯，而得到標題化合物。Example 217 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethane 2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile was synthesized in accordance with Example 161 (steps 1 to 5), by using 3-[(2,3-difluoro-6-nitro-anilino)methyl]pentane-3 -Alcohol instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol, and the tertiary butyl (( 1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxole Alk-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate tert-butyl N-[ (3-Internal)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane Pentaboran-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate to obtain the title compound.

實施例218　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 218 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-1- (2-Ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked The synthesis of benzene]-4-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), by using 3-(aminomethyl)pentane-3-ol instead of 1-amine 2-methyl-propan-2-ol to obtain the title compound.

實施例219　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-氯-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 219 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-1-(2-ethyl-2-hydroxybutyl)-6-fluoro- The synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was carried out in Example 209 (Step 1~ 5) As the standard, by using 3-(aminomethyl)pentane-3-ol instead of 1-amino-2-methyl-propan-2-ol, and using the result obtained in step 1 of Example 37 Tertiary Butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4 '-Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'- Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例220　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-氯-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 220 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-1-(2-ethyl 2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4 -The synthesis of carbonitrile is based on Example 209 (steps 1 to 5), by using 3-(aminomethyl)pentane-3-ol instead of 1-amino-2-methyl-propane-2 -Alcohol, and the tertiary butyl N-[(3-internal)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl ]Carbamate tert-butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl) Carbamate-isomer-X to give the title compound.

實施例221　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 221 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-1- (2-Ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked The synthesis of benzene]-4-carbonitrile is based on Example 209 (steps 1 to 5), by using 3-(aminomethyl)pentane-3-ol instead of 1-amino-2-methyl -Propane-2-ol, and the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo [2.2.1]Heptan-2-yl)carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-aza Bicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例222　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-3-羧酸-異構物-X之合成(步驟1)將實施例171步驟1所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)吲哚-5-基]苯甲酸 250mg溶解於THF 2.24mL中。於室溫添加HATU 234mg、實施例202步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 125mg、TEA 0.156mL，於50℃攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。Example 222 ``5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indole-3-carboxylic acid-isomer -X synthesis (step 1) The 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl) obtained in step 1 of Example 171 250 mg of propyl-propyl)indol-5-yl]benzoic acid was dissolved in 2.24 mL of THF. Add 234 mg of HATU and the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamic acid obtained in step 2 of Example 202 at room temperature Ester-isomer-X 125 mg, TEA 0.156 mL, and stirring at 50°C for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro- 6-(6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-nitrogen Heterobicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X.

(步驟2)將前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 289mg溶解於DMF 4.50mL中。於室溫添加N-碘琥珀醯亞胺 120mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-3-碘-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(Step 2) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-( 2-Hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptane- 2-yl) carbamate-isomer-X 289 mg was dissolved in 4.50 mL of DMF. 120 mg of N-iodosuccinimide was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' -Fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-3-iodo-1H-indol-5-yl)-[1,1'-biphenyl]-3 -Carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X.

(步驟3)將前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-3-碘-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 20mg、PdCl2 (PPh3)2 0.92mg懸浮於1-甲基-2-吡咯啶酮　0.2mL中。於室溫添加N,N-二乙基乙醇胺 0.0173mL，進行CO取代，於100℃攪拌1小時。於反應液中添加t-BuOH 0.2mL、2當量濃度氫氧化鈉水溶液 0.2mL，於室溫下終夜攪拌。添加MTBE，分離水層。對水層添加鹽酸而使其成為酸性之後，以MTBE萃取。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。對殘渣添加乙腈 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL，攪拌10分鐘。濃縮反應液、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-( 2-hydroxy-2-methylpropyl)-3-iodo-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X 20 mg, PdCl 2 (PPh3) 2 0.92 mg were suspended in 0.2 mL of 1-methyl-2-pyrrolidone. At room temperature, 0.0173 mL of N,N-diethylethanolamine was added to perform CO substitution, and the mixture was stirred at 100°C for 1 hour. Add 0.2 mL of t-BuOH and 0.2 mL of 2 equivalent sodium hydroxide aqueous solution to the reaction solution, and stir overnight at room temperature. Add MTBE and separate the water layer. After adding hydrochloric acid to the water layer to make it acidic, it was extracted with MTBE. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. To the residue, 0.5 mL of acetonitrile and 0.5 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added, and the mixture was stirred for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例223　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲唑-3-羧酸-異構物-X之合成(步驟1)將實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 350mg、5-溴-6-氟-1-甲基-吲唑　186mg懸浮於1,4-二噁烷2.08mL中。於室溫添加Pd(dba)2 28.7mg、X-phos 47.6mg、磷酸三鉀 397mg，進行脫氣、氮取代。在氮環境氣體下，於外溫100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(步驟2)以實施例212(步驟2~3)為準，藉由使用前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 223 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indazole-3-carboxylic acid-isomer-X synthesis (step 1) will be implemented Example 207 The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl) obtained in step 2 -1,3,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptane-2- Yl) carbamate-isomer-X 350 mg, 5-bromo-6-fluoro-1-methyl-indazole 186 mg were suspended in 1,4-dioxane 2.08 mL. Pd(dba) 2 28.7 mg, X-phos 47.6 mg, and tripotassium phosphate 397 mg were added at room temperature to degas and replace with nitrogen. Under a nitrogen atmosphere, stir overnight at an external temperature of 100°C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3) '-Fluoro-6-(6-fluoro-1-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X. (Step 2) Based on Example 212 (Steps 2 to 3), by using the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano- 3'-fluoro-6-(6-fluoro-1-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2. 1) Heptan-2-yl) carbamate-isomer-X instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro- 6-(6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-nitrogen Heterobicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例224　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X之合成(步驟1)將實施例207(步驟2)所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 350mg、5-溴-6-氟-1-甲基-吲哚　185mg懸浮於1,4-二噁烷2.08mL中。於室溫添加Pd(dba)2 28.7mg、X-phos 47.6mg、磷酸三鉀 397mg，進行脫氣、氮取代。在氮環境氣體下，於外溫100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。Example 224 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid-isomer-X synthesis (step 1) will be implemented Example 207 (Step 2) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptane- 2-yl) carbamate-isomer-X 350 mg and 5-bromo-6-fluoro-1-methyl-indole 185 mg were suspended in 2.08 mL of 1,4-dioxane. Pd(dba) 2 28.7 mg, X-phos 47.6 mg, and tripotassium phosphate 397 mg were added at room temperature to degas and replace with nitrogen. Under a nitrogen atmosphere, stir overnight at an external temperature of 100°C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3) '-Fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X.

(步驟2)將前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 209mg溶解於DMF 3.6mL中。於室溫添加N-碘琥珀醯亞胺 121mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-3-碘-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(Step 2) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl) obtained in the aforementioned step 1 -1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-iso Structure-X 209mg was dissolved in DMF 3.6mL. 121 mg of N-iodosuccinimide was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' -Fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[ 2.2.1] Heptan-2-yl) carbamate-isomer-X.

(步驟3)將前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-3-碘-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 211mg、PdCl2 (PPh3 )2 10.5mg懸浮於1-甲基-2-吡咯啶酮　2.11mL中。於室溫添加N,N-二乙基乙醇胺 0.197mL，進行CO取代，於100℃攪拌1小時。於反應液中添加t-BuOH 0.2mL、2當量濃度氫氧化鈉水溶液 0.2mL，於室溫下終夜攪拌。添加MTBE，分離水層。對水層添加鹽酸而使其成為酸性之後，以MTBE萃取。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑，而得到5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X。(步驟4)對前述步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X 10mg添加乙腈 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL，攪拌10分鐘。濃縮反應液、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo -1-Methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate Ester-isomer-X 211 mg, PdCl 2 (PPh 3 ) 2 10.5 mg were suspended in 2.11 mL of 1-methyl-2-pyrrolidone. 0.197 mL of N,N-diethylethanolamine was added at room temperature, CO substitution was performed, and the mixture was stirred at 100°C for 1 hour. Add 0.2 mL of t-BuOH and 0.2 mL of 2 equivalent sodium hydroxide aqueous solution to the reaction solution, and stir overnight at room temperature. Add MTBE and separate the water layer. After adding hydrochloric acid to the water layer to make it acidic, it was extracted with MTBE. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off to obtain 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo [2.2.1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H- Indole-3-carboxylic acid-isomer-X. (Step 4) The 5-(5-((1S,2S,4R)-rel-2-((3rd butoxycarbonyl)amino)-7-azabicyclo[2.2. 1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole- Add 0.5 mL of acetonitrile and 0.5 mL of 4-eq hydrochloric acid-1,4-dioxane solution to 10 mg of 3-carboxylic acid-isomer-X, and stir for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例225　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6-氟-1H-吲唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成將實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 40mg、實施例204步驟1所得到的3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇 29.2mg懸浮於1,4-二噁烷0.5mL中。於室溫添加Pd(dba)2 3.3mg、X-phos 5.5mg、磷酸三鉀 45.4mg，於100℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。將殘渣溶解於乙腈 0.5 mL中。於室溫添加4當量濃度鹽酸-1,4-二噁烷溶液0.5mL，於室溫攪拌5分鐘。濃縮反應液、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 225 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethane 2-hydroxybutyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in step 1 of Example 213 The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamic acid 40 mg of ester, 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentane-3-ol 29.2 mg obtained in step 1 of Example 204 were suspended in 1,4-dioxane 0.5mL in. Pd(dba) 2 3.3 mg, X-phos 5.5 mg, and tripotassium phosphate 45.4 mg were added at room temperature, and the mixture was stirred at 100°C for 1 hour. The reaction liquid was filtered, and the solvent was distilled off. The residue was dissolved in 0.5 mL of acetonitrile. Add 0.5 mL of 4 equivalents of hydrochloric acid-1,4-dioxane solution at room temperature, and stir at room temperature for 5 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例226　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1,3-二氫異苯并呋喃-5-基)-[1,1’-聯苯]-4-甲腈-異構物-X之合成(步驟1)將甲基　5-溴-4-氟-2-碘-苯甲酸酯 2g溶解於二乙基醚55.7mL中。於0℃添加2.0M LiBH4　THF溶液6.13mL、MeOH 0.56mL，於0℃攪拌1小時。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到(5-溴-4-氟-2-碘-苯基)甲醇。Example 226 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1,3-dihydroisobenzofuran-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer Synthesis of Compound-X (Step 1) Dissolve 2 g of methyl 5-bromo-4-fluoro-2-iodo-benzoate in 55.7 mL of diethyl ether. 6.13 mL of 2.0M LiBH4"THF solution and 0.56 mL of MeOH were added at 0°C, and the mixture was stirred at 0°C for 1 hour. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain (5-bromo-4-fluoro-2-iodo-phenyl)methanol.

(步驟2)將前述步驟1所得到的(5-溴-4-氟-2-碘-苯基)甲醇 1.39g、3,4-二氫-2H-哌喃　0.419mL溶解於DCM 8.4mL中。於室溫添加對甲苯磺酸吡啶鎓 106mg，於室溫徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到2-[(5-溴-4-氟-2-碘-苯基)甲氧基]四氫哌喃。(Step 2) Dissolve 1.39g of (5-bromo-4-fluoro-2-iodo-phenyl)methanol and 0.419mL of 3,4-dihydro-2H-piperan obtained in step 1 above in 8.4mL of DCM . 106 mg of pyridinium p-toluenesulfonate was added at room temperature, and the mixture was stirred at room temperature overnight. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]tetrahydropiper Mutter.

(步驟3)將前述步驟2所得到的2-[(5-溴-4-氟-2-碘-苯基)甲氧基]四氫哌喃　1.5　g、PdCl2 (PPh3 )2 130mg、CuI　34mg懸浮於THF 18mL中。於室溫添加TEA 18mL、2-甲基-3-丁炔-2-醇 0.42mL，於室溫攪拌4小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-[4-溴-5-氟-2-(四氫哌喃-2-基氧基甲基)苯基]-2-甲基-3-丁炔-2-醇。(Step 3) 1.5 g of 2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]tetrahydropiperan obtained in step 2 above, PdCl 2 (PPh 3 ) 2 130 mg, 34 mg of CuI was suspended in 18 mL of THF. 18 mL of TEA and 0.42 mL of 2-methyl-3-butyn-2-ol were added at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-[4-bromo-5-fluoro-2-(tetrahydropiperan-2-yloxymethyl) ) Phenyl]-2-methyl-3-butyn-2-ol.

(步驟4)將實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 150mg、前述步驟3所得到的4-[4-溴-5-氟-2-(四氫哌喃-2-基氧基甲基)苯基]-2-甲基-3-丁炔-2-醇 129mg懸浮於1,4-二噁烷0.89mL中。於室溫添加Pd(dba)2 12.3mg、X-phos 20.4mg，於100℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣。將殘渣溶解於THF 0.92mL、水 0.46mL中。於室溫添加對甲苯磺酸一水合物　6.9mg，於70℃攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-　rel-7-(4’’-氰基-2,3’’-二氟-4-(3-羥基-3-甲基1-丁炔-1-基)-5-(羥基甲基)-[1,1’:2’,1’’-聯三苯]-4’-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X。(步驟5)將前述步驟4所得到的第三丁基　((1S,2S,4R)-　rel-7-(4’’-氰基-2,3’’-二氟-4-(3-羥基-3-甲基1-丁炔-1-基)-5-(羥基甲基)-[1,1’:2’,1’’-聯三苯]-4’-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 30mg溶解於1,4-二噁烷0.24mL中。於室溫添加1.0M TBAF　THF溶液 0.14mL，於100℃攪拌1小時。於反應液中添加EtOH　0.12mL、10%Pd/C　30mg，進行氫取代，於70℃攪拌30分鐘。過濾反應液並濃縮濾液。將殘渣溶解於THF中。於室溫添加TEA 0.013mL、DMAP 1.1mg、Boc2O　20.4mg，於70℃攪拌1小時。添加乙酸乙酯，依序以約0.5mol/L　磷酸洗淨5次、以飽和食鹽水洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。將殘渣溶解於乙腈 0.5mL中。於室溫添加4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL，於室溫攪拌5分鐘。以LCMS確認反應結束後，蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5) obtained in step 2 of Example 207 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl)carbamate-isomer-X 150mg, 4-[4-bromo-5-fluoro-2-(tetrahydropiperan-2-yloxy) obtained in step 3 above 129 mg of methyl)phenyl]-2-methyl-3-butyn-2-ol was suspended in 0.89 mL of 1,4-dioxane. Pd(dba) 2 12.3 mg and X-phos 20.4 mg were added at room temperature, and the mixture was stirred at 100°C for 1 hour. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The residue was dissolved in 0.92 mL of THF and 0.46 mL of water. 6.9 mg of p-toluenesulfonic acid monohydrate was added at room temperature, and the mixture was stirred at 70°C for 1 hour. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4''-cyano-2 ,3''-Difluoro-4-(3-hydroxy-3-methyl1-butyn-1-yl)-5-(hydroxymethyl)-[1,1':2',1''- Terphenyl]-4'-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X. (Step 5) The tertiary butyl ((1S,2S,4R)-rel-7-(4''-cyano-2,3''-difluoro-4-(3- Hydroxy-3-methyl-1-butyn-1-yl)-5-(hydroxymethyl)-[1,1':2',1''-terphenyl]-4'-carbonyl)-7- Azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X 30mg was dissolved in 0.24mL of 1,4-dioxane. 0.14 mL of 1.0M TBAF THF solution was added at room temperature, and the mixture was stirred at 100°C for 1 hour. To the reaction solution, 0.12 mL of EtOH and 30 mg of 10% Pd/C were added to perform hydrogen substitution, and the mixture was stirred at 70° C. for 30 minutes. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in THF. TEA 0.013 mL, DMAP 1.1 mg, and Boc2O 20.4 mg were added at room temperature, and the mixture was stirred at 70°C for 1 hour. Add ethyl acetate, wash with about 0.5mol/L phosphoric acid for 5 times, wash with saturated brine, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was dissolved in 0.5 mL of acetonitrile. Add 0.5 mL of 4 equivalents of hydrochloric acid-1,4-dioxane solution at room temperature, and stir at room temperature for 5 minutes. After confirming completion of the reaction by LCMS, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例227　5’-((S)-3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-1,3-二氫異苯并呋喃-5-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例41步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 400mg、實施例226步驟3所得到的4-[4-溴-5-氟-2-(四氫哌喃-2-基氧基甲基)苯基]-2-甲基-3-丁炔-2-醇 456mg懸浮於1,4-二噁烷3.15mL中。於室溫添加Pd(dba)2 43.5mg、X-phos 144mg、磷酸三鉀 601mg，於100℃攪拌1小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣。將殘渣溶解於THF 1.62mL中。於室溫添加水0.81mL、對甲苯磺酸一水合物　12.3mg，於70℃攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　3-(4-氰基-3-氟-苯基)-4-[2-氟-5-(羥基甲基)-4-(3-羥基-3-甲基-1-丁烯基)苯基]苯甲酸酯。Example 227 5'-((S)-3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)- Synthesis of 1,3-dihydroisobenzofuran-5-yl)-[1,1'-biphenyl]-4-carbonitrile (step 1) The tertiary butyl 3 obtained in step 1 of Example 41 -(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl 400 mg of ester, 4-[4-bromo-5-fluoro-2-(tetrahydropiperan-2-yloxymethyl)phenyl]-2-methyl-3- obtained in step 3 of Example 226 456 mg of butyn-2-ol was suspended in 3.15 mL of 1,4-dioxane. Pd(dba) 2 43.5 mg, X-phos 144 mg, and tripotassium phosphate 601 mg were added at room temperature, and the mixture was stirred at 100°C for 1 hour. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in 1.62 mL of THF. 0.81 mL of water and 12.3 mg of p-toluenesulfonic acid monohydrate were added at room temperature, and the mixture was stirred at 70°C for 1 hour. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro -5-(hydroxymethyl)-4-(3-hydroxy-3-methyl-1-butenyl)phenyl]benzoate.

(步驟2)將前述步驟1所得到的第三丁基　3-(4-氰基-3-氟-苯基)-4-[2-氟-5-(羥基甲基)-4-(3-羥基-3-甲基-1-丁烯基)苯基]苯甲酸酯 90mg溶解於1,4-二噁烷0.9mL中。於室溫添加1.0M TBAF　THF溶液0.54mL，於100℃攪拌2小時。於反應液中添加EtOH　0.30mL、10%Pd/C　90mg，進行氫取代，於70℃徹夜攪拌。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣。將殘渣溶解於THF 1.0mL中。於室溫添加12當量濃度鹽酸0.5mL，於室溫攪拌1.5小時。添加MTBE，以2當量濃度氫氧化鈉水溶液萃取2次，於水層加入2當量濃度鹽酸而使其成為酸性，以MTBE萃取2次。以飽和食鹽水依序洗淨有機層，以無水硫酸鈉乾燥後蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)-1,3-二氫異苯并呋喃-5-基]苯甲酸。(Step 2) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-5-(hydroxymethyl)-4-(3 90 mg of -hydroxy-3-methyl-1-butenyl)phenyl]benzoate was dissolved in 0.9 mL of 1,4-dioxane. 0.54 mL of 1.0M TBAF"THF solution was added at room temperature, and the mixture was stirred at 100°C for 2 hours. EtOH"0.30mL and 10%Pd/C"90mg were added to the reaction liquid, hydrogen substitution was carried out, and the mixture was stirred at 70°C overnight. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The residue was dissolved in 1.0 mL of THF. Add 0.5 mL of 12 equivalents of hydrochloric acid at room temperature, and stir at room temperature for 1.5 hours. MTBE was added, extraction was performed twice with 2 equivalents of sodium hydroxide aqueous solution, 2 equivalents of hydrochloric acid was added to the water layer to make it acidic, and extracted with MTBE twice. The organic layer was washed sequentially with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-( 2-Hydroxy-2-methyl-propyl)-1,3-dihydroisobenzofuran-5-yl]benzoic acid.

(步驟3)將前述步驟2所得到的3-(4-氰基-3-氟-苯基)-4-[6-氟-1-(2-羥基-2-甲基-丙基)-1,3-二氫異苯并呋喃-5-基]苯甲酸 10mg溶解於THF 0.5mL中。於室溫添加HATU 9.31mg、第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯 43.5mg、TEA 6.2μL，於50℃攪拌1小時。蒸餾去除溶劑，添加MeOH 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液0.5mL，於室溫攪拌30分鐘。蒸餾去除溶劑，以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 3) The 3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-(2-hydroxy-2-methyl-propyl)- 10 mg of 1,3-dihydroisobenzofuran-5-yl]benzoic acid was dissolved in 0.5 mL of THF. At room temperature, 9.31 mg of HATU, 43.5 mg of tert-butyl "N-[(3S)-pyrrolidin-3-yl]carbamate, and 6.2 μL of TEA were added, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, 0.5 mL of MeOH and 0.5 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例228　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，而得到標題化合物。Example 228 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-(2-hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- The synthesis of biphenyl]-4-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), by using 1,3-difluoro-2-methyl-4-nitro-benzene Instead of 2-chloro-1,3-difluoro-4-nitro-benzene, the title compound was obtained.

實施例229　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(5-氟-3-(2-羥基-2-甲基丙基)苯并[d]異噁唑-6-基)-[1,1’-聯苯]-4-甲腈之合成(步驟1)將實施例179步驟2所得到的1-(4-溴-5-氟-2-羥基苯基)乙酮150mg溶解於THF 3.2mL中。於-25℃添加鋰二異丙基醯胺(1.0M THF溶液)3.2mL，並於-25℃攪拌1小時。-冷卻至40℃，添加丙酮 0.118mL，於-40℃攪拌1小時。添加磷酸水溶液之後，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(4-溴-5-氟-2-羥基-苯基)-3-羥基-3-甲基-丁烷-1-酮。Example 229 (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-(2-hydroxy-2-methylpropyl)benzene And [d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile synthesis (step 1) The 1-(4-bromo-5 obtained in step 2 of Example 179) 150 mg of -fluoro-2-hydroxyphenyl)ethanone was dissolved in 3.2 mL of THF. 3.2 mL of lithium diisopropylamide (1.0M THF solution) was added at -25°C, and stirred at -25°C for 1 hour. -Cool to 40°C, add 0.118 mL of acetone, and stir at -40°C for 1 hour. After the phosphoric acid aqueous solution was added, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)-3-hydroxy-3-methyl -Butan-1-one.

(步驟2)將前述步驟1所得到的1-(4-溴-5-氟-2-羥基-苯基)-3-羥基-3-甲基-丁烷-1-酮　60mg、羥基胺鹽酸鹽 28.6mg、乙酸鈉25.4mg溶解於甲醇0.69mL中，於60℃徹夜攪拌。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。將殘渣溶解於THF 0.69mL中，添加N,N’-羰基二咪唑 36.8mg、TEA 0.037mL、於70℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(6-溴-5-氟-1,2-苯并噁唑-3-基)-2-甲基-丙烷-2-醇。(Step 2) Combine 60 mg of 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)-3-hydroxy-3-methyl-butane-1-one obtained in step 1 above, hydroxylamine salt The acid salt 28.6 mg and sodium acetate 25.4 mg were dissolved in 0.69 mL of methanol, and stirred at 60°C overnight. Add MTBE, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was dissolved in 0.69 mL of THF, 36.8 mg of N,N'-carbonyldiimidazole and 0.037 mL of TEA were added, and the mixture was stirred at 70°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-bromo-5-fluoro-1,2-benzoxazole-3- Yl)-2-methyl-propan-2-ol.

(步驟3)以實施例37(步驟1~3)為準，藉由使用前述步驟2所得到的1-(6-溴-5-氟-1,2-苯并噁唑-3-基)-2-甲基-丙烷-2-醇來代替1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 3) According to Example 37 (Steps 1 to 3), by using the 1-(6-bromo-5-fluoro-1,2-benzoxazol-3-yl) obtained in step 2 above -2-methyl-propan-2-ol was substituted for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to obtain the title compound.

實施例230　2-(5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙醯胺之合成(步驟1)將實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 100mg、實施例207步驟1所得到的乙基　2-(5-溴-6-氟-吲哚-1-基)乙酸酯 69.5mg懸浮於1,4-二噁烷0.59mL中。於室溫添加Pd(dba)2 8.2mg、X-phos 13.6mg、磷酸三鉀 113mg，進行脫氣、氮取代。在氮環境氣體下，於外溫100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣。將殘渣溶解於MeOH 1.0mL中，添加5當量濃度氫氧化鈉水溶液 1.0mL，攪拌1小時。添加MTBE，於水層萃取。以鹽酸使水層成為酸性，添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑，而得到2-(5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸。Example 230 2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano -3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetamide synthesis (step 1) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamic acid 100 mg of the ester and 69.5 mg of ethyl 2-(5-bromo-6-fluoro-indol-1-yl) acetate obtained in step 1 of Example 207 were suspended in 0.59 mL of 1,4-dioxane. Pd(dba) 2 8.2 mg, X-phos 13.6 mg, and tripotassium phosphate 113 mg were added at room temperature for degassing and nitrogen substitution. Under a nitrogen atmosphere, stir overnight at an external temperature of 100°C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in 1.0 mL of MeOH, and 1.0 mL of a 5-N sodium hydroxide aqueous solution was added, followed by stirring for 1 hour. Add MTBE and extract in the water layer. The aqueous layer was made acidic with hydrochloric acid, MTBE was added, washed with water and saturated brine in order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 2-(5-(5-((1S,2S, 4R)-rel-2-((Third-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[ 1,1'-Biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid.

(步驟2)將前述步驟1所得到的2-(5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸 10mg溶解於THF 0.32mL中。添加N,N’-羰基二咪唑 5.2mg，於室溫攪拌20分鐘、添加28%氨水 0.06mL，於室溫攪拌20分鐘。蒸餾去除溶劑，對殘渣添加乙腈 0.2mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.2mL，攪拌30分鐘。蒸餾去除溶劑，以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 2) The 2-(5-(5-((1S,2S,4R)-rel-2-((third butoxycarbonyl)amino)-7-azabicyclo [2.2.1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indole-1- 10 mg of acetic acid was dissolved in 0.32 mL of THF. Add 5.2 mg of N,N'-carbonyldiimidazole, stir at room temperature for 20 minutes, add 0.06 mL of 28% ammonia water, and stir at room temperature for 20 minutes. The solvent was distilled off, 0.2 mL of acetonitrile and 0.2 mL of 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 30 minutes. The solvent was distilled off, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例231　2-(5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)-N-甲基乙醯胺之合成將實施例230步驟1所得到的2-(5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)乙酸 10mg溶解於THF 0.064mL中。於室溫添加HATU 6.7mg、甲基胺鹽酸鹽 2.2mg、TEA 6.7μL，於50℃攪拌1小時。蒸餾去除溶劑，對殘渣添加乙腈 1.0mL、4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL並攪拌10分鐘。蒸餾去除溶劑，將殘渣溶解於DMSO中，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。Example 231 "2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano Synthesis of -3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)-N-methylacetamide Step 1 of Example 230 The resulting 2-(5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane- 7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid 10mg dissolved in THF 0.064 mL in. 6.7 mg of HATU, 2.2 mg of methylamine hydrochloride, and 6.7 μL of TEA were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, 1.0 mL of acetonitrile and 1.0 mL of 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 10 minutes. The solvent was distilled off, the residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例232　2-(5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1H-吲哚-1-基)-N,N-二甲基乙醯胺之合成以實施例231為準，藉由使用二甲基胺鹽酸鹽來代替甲基胺鹽酸鹽，而得到標題化合物。Example 232 "2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano The synthesis of -3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)-N,N-dimethylacetamide is taken as an example 231 was the standard, and the title compound was obtained by using dimethylamine hydrochloride instead of methylamine hydrochloride.

實施例233　2-(4’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’’-氰基-2,3’’-二氟-[1,1’:2’,1’’-聯三苯]-4-基)乙醯胺之合成(步驟1)將2-(4-溴-3-氟-苯基)乙酸 600mg溶解於THF 10.3mL中。於室溫添加HATU 1.08g、NH4 Cl　275.4mg、TEA 1.08mL，於50℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到2-(4-溴-3-氟-苯基)乙醯胺。(步驟2)以實施例225為準，藉由使用前述步驟1所得到的2-(4-溴-3-氟-苯基)乙醯胺來代替3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇，而得到標題化合物。Example 233 2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4''-cyano- Synthesis of 2,3''-difluoro-[1,1':2',1''-terphenyl]-4-yl)acetamide (Step 1) The 2-(4-bromo-3- 600 mg of fluoro-phenyl)acetic acid was dissolved in 10.3 mL of THF. 1.08 g of HATU, 275.4 mg of NH 4 Cl, and 1.08 mL of TEA were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)acetamide. (Step 2) Based on Example 225, the 2-(4-bromo-3-fluoro-phenyl)acetamide obtained in step 1 above was used instead of 3-[(5-bromo-6-fluoro -Indazol-1-yl)methyl]pentane-3-ol to obtain the title compound.

實施例234　2-(4’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’’-氰基-2,3’’-二氟-[1,1’:2’,1’’-聯三苯]-4-基)-N-甲基乙醯胺之合成(步驟1)將2-(4-溴-3-氟-苯基)乙酸 600mg溶解於THF 10.3mL中。於室溫添加HATU 1.08g、甲基胺(ca.9.8　mol/L　MeOH溶液) 0.525mL、TEA 1.08mL，於50℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到2-(4-溴-3-氟-苯基)-N-甲基-乙醯胺。(步驟2)以實施例225為準，藉由使用前述步驟1所得到的2-(4-溴-3-氟-苯基)-N-甲基-乙醯胺來代替3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇，而得到標題化合物。Example 234 ``2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4''-cyano- Synthesis of 2,3''-difluoro-[1,1':2',1''-terphenyl]-4-yl)-N-methylacetamide (step 1) -Bromo-3-fluoro-phenyl)acetic acid 600 mg was dissolved in 10.3 mL of THF. 1.08 g of HATU, 0.525 mL of methylamine (ca.9.8 "mol/L" MeOH solution), and 1.08 mL of TEA were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)-N-methyl-acetamide. (Step 2) Based on Example 225, the 2-(4-bromo-3-fluoro-phenyl)-N-methyl-acetamide obtained in step 1 above was used instead of 3-[(5 -Bromo-6-fluoro-indazol-1-yl)methyl]pentane-3-ol to obtain the title compound.

實施例235　2-(4’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’’-氰基-2,3’’-二氟-[1,1’:2’,1’’-聯三苯]-4-基)-N,N-二甲基乙醯胺之合成(步驟1)將2-(4-溴-3-氟-苯基)乙酸 600mg溶解於THF 10.3mL中。於室溫添加HATU 1.08g、二甲基胺鹽酸鹽419.9mg、TEA 1.08mL，於50℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到2-(4-溴-3-氟-苯基)-N,N-二甲基-乙醯胺。(步驟2)以實施例225為準，藉由使用前述步驟1所得到的2-(4-溴-3-氟-苯基)-N,N-二甲基-乙醯胺來代替3-[(5-溴-6-氟-吲唑-1-基)甲基]戊烷-3-醇，而得到標題化合物。Example 235 ``2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4''-cyano- Synthesis of 2,3''-difluoro-[1,1':2',1''-terphenyl]-4-yl)-N,N-dimethylacetamide (step 1) 600 mg of -(4-bromo-3-fluoro-phenyl)acetic acid was dissolved in 10.3 mL of THF. 1.08 g of HATU, 419.9 mg of dimethylamine hydrochloride, and 1.08 mL of TEA were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-acetate amine. (Step 2) Based on Example 225, the 2-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-acetamide obtained in step 1 above was used instead of 3- [(5-Bromo-6-fluoro-indazol-1-yl)methyl]pentane-3-ol to obtain the title compound.

實施例236　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧基醯胺-異構物-X之合成將實施例224步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X 10mg溶解於THF 0.32mL中。添加N,N’-羰基二咪唑 5.2mg，於室溫攪拌20分鐘，添加28%氨水 0.1mL，於室溫攪拌20分鐘。蒸餾去除溶劑，對殘渣添加乙腈 0.2mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.2mL，攪拌30分鐘。蒸餾去除溶劑，以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。Example 236 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxamide-isomer-X Synthesis Steps in Example 224 3 The resulting 5-(5-((1S,2S,4R)-rel-2-((third butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7- Carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid-isomer 10mg of substance-X was dissolved in 0.32mL of THF. Add 5.2 mg of N,N'-carbonyldiimidazole, stir at room temperature for 20 minutes, add 0.1 mL of 28% ammonia water, and stir at room temperature for 20 minutes. The solvent was distilled off, 0.2 mL of acetonitrile and 0.2 mL of 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 30 minutes. The solvent was distilled off, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例237　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-N,1-二甲基-1H-吲哚-3-羧基醯胺-異構物-X之合成將實施例224步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X 10mg溶解於THF 0.064mL中。於室溫添加HATU 6.7mg、甲基胺鹽酸鹽 2.2mg、TEA 6.7μL，於50℃攪拌1小時。蒸餾去除溶劑，對殘渣添加乙腈 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL並攪拌10分鐘。蒸餾去除溶劑，將殘渣溶解於DMSO中，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。Example 237 ``5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,1-dimethyl-1H-indole-3-carboxyamide-isomer-X synthesis will be implemented Example 224 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane obtained in step 3 -7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid -Isomer-X 10mg was dissolved in THF 0.064mL. 6.7 mg of HATU, 2.2 mg of methylamine hydrochloride, and 6.7 μL of TEA were added at room temperature, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off, 0.5 mL of acetonitrile and 0.5 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 10 minutes. The solvent was distilled off, the residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例238　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-N,N,1-三甲基-1H-吲哚-3-羧基醯胺-異構物-X之合成以實施例237為準，藉由使用二甲基胺鹽酸鹽來代替甲基胺鹽酸鹽，而得到標題化合物。Example 238 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,N,1-trimethyl-1H-indole-3-carboxyamide-isomer-X synthesis Based on Example 237, the title compound was obtained by using dimethylamine hydrochloride instead of methylamine hydrochloride.

實施例239　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成　以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 239 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)- 7-Methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 209 (Step 1 ~5) shall prevail, by using 1,3-difluoro-2-methyl-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and use Example 37 The tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl) obtained in step 1 Yl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl ((1S,2S,4R) -rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例240　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 240 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- (2-Hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]- The synthesis of 4-carbonitrile was based on Example 209 (steps 1 to 5), and 1,3-difluoro-2-methyl-4-nitro-benzene was used instead of 2-chloro-1,3- Difluoro-4-nitro-benzene, and the tertiary butyl N-[(3-ino)-8-[3-(4-cyano-3-fluoro-phenyl obtained in step 3 of Example 41) )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1 ]Octan-3-yl]carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2. 1] Heptan-2-yl) carbamate-isomer-X to obtain the title compound.

實施例241　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-(2-羥基-2-甲基丙基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 241 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-(2-hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- The synthesis of biphenyl]-4-carbonitrile was based on Example 209 (steps 1 to 5), by using 1,3-difluoro-2-methyl-4-nitro-benzene instead of 2-chloro- 1,3-Difluoro-4-nitro-benzene, and the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' -Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl )-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3 '-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3- Carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例242　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸之合成(步驟1)將實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 200mg、5-溴-6-氟-1-甲基-吲哚　105.6mg懸浮於1,4-二噁烷1.19mL中。於室溫添加Pd(dba)2 16.4mg、X-phos 27.2mg、磷酸三鉀 226.9mg，進行脫氣、氮取代。在氮環境氣體下，於外溫100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯。Example 242 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' Synthesis of -fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid (step 1) Obtained in step 1 of Example 213 The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate 200 mg and 105.6 mg of 5-bromo-6-fluoro-1-methyl-indole were suspended in 1.19 mL of 1,4-dioxane. Pd(dba) 2 16.4 mg, X-phos 27.2 mg, and tripotassium phosphate 226.9 mg were added at room temperature for degassing and nitrogen substitution. Under a nitrogen atmosphere, stir overnight at an external temperature of 100°C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3) '-Fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate.

(步驟2)將前述步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯209mg溶解於DMF 3.6mL中。於室溫添加N-碘琥珀醯亞胺 121mg，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-3-碘-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯。(Step 2) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl) obtained in the aforementioned step 1 -1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate 209mg dissolved In DMF 3.6mL. 121 mg of N-iodosuccinimide was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' -Fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[ 2.2.1] Heptan-2-yl) carbamate.

(步驟3)將前述步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(6-氟-3-碘-1-甲基-1H-吲哚-5-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 211mg、PdCl2 (PPh3 )2 10.5mg懸浮於1-甲基-2-吡咯啶酮　2.11mL中。於室溫添加N,N-二乙基乙醇胺 0.197mL，進行CO取代，於100℃攪拌1小時。於反應液中添加t-BuOH 0.2mL、2當量濃度氫氧化鈉水溶液 0.2mL，於室溫下終夜攪拌。添加MTBE，分離水層。對水層添加鹽酸而使其成為酸性之後，以MTBE萃取。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑，而得到5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸。(Step 3) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo -1-Methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate 211 mg of acid ester and 10.5 mg of PdCl 2 (PPh 3 ) 2 were suspended in 2.11 mL of 1-methyl-2-pyrrolidone. 0.197 mL of N,N-diethylethanolamine was added at room temperature, CO substitution was performed, and the mixture was stirred at 100°C for 1 hour. Add 0.2 mL of t-BuOH and 0.2 mL of 2 equivalent sodium hydroxide aqueous solution to the reaction solution, and stir overnight at room temperature. Add MTBE and separate the water layer. After adding hydrochloric acid to the water layer to make it acidic, it was extracted with MTBE. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off to obtain 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo [2.2.1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H- Indole-3-carboxylic acid.

(步驟4)對前述步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸 10mg添加乙腈 0.5mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.5mL，攪拌10分鐘。濃縮反應液、以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) The 5-(5-((1S,2S,4R)-rel-2-((3rd butoxycarbonyl)amino)-7-azabicyclo[2.2. 1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole- To 10 mg of 3-carboxylic acid, 0.5 mL of acetonitrile and 0.5 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added and stirred for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例243　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-N,1-二甲基-1H-吲哚-3-羧基醯胺之合成以實施例237為準，藉由使用實施例242步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸來代替5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X，而得到標題化合物。Example 243 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' The synthesis of -fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,1-dimethyl-1H-indole-3-carboxyamide is based on Example 237. By using the 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1 ]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3 -Carboxylic acid instead of 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7 -Carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid-iso Construct-X, and obtain the title compound.

實施例244　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-N,N,1-三甲基-1H-吲哚-3-羧基醯胺之合成以實施例237為準，藉由使用實施例242步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸來代替5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X，且使用二甲基胺鹽酸鹽來代替甲基胺鹽酸鹽，而得到標題化合物。Example 244 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' The synthesis of -fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,N,1-trimethyl-1H-indole-3-carboxyamide is based on Example 237 , By using the 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2 .1]Heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole -3-carboxylic acid instead of 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane -7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid -Isomer-X, and use dimethylamine hydrochloride instead of methylamine hydrochloride to obtain the title compound.

實施例245　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧基醯胺之合成以實施例236為準，藉由使用實施例242步驟3所得到的5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸來代替5-(5-((1S,2S,4R)-rel-2-((第三丁氧基羰基)胺基)-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-甲基-1H-吲哚-3-羧酸-異構物-X，而得到標題化合物。Example 245 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' The synthesis of -fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxyamide is based on Example 236, and is implemented by using Example 242 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane obtained in step 3 -7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid Instead of 5-(5-((1S,2S,4R)-rel-2-((tertiary butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl) -4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid-isomer- X to obtain the title compound.

實施例246　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-(二氟甲基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，而得到標題化合物。Example 246``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl) Yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1 ,1'-Biphenyl]-4-carbonitrile-isomer-X was synthesized according to Example 209 (steps 1 to 5), by using 2-(difluoromethyl)-1,3-di Fluoro-4-nitro-benzene was substituted for 2-chloro-1,3-difluoro-4-nitro-benzene to obtain the title compound.

實施例247　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-7-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用THF來代替EtOH，而得到標題化合物。Example 247 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3 ] The synthesis of triazole-7-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), and 2,6-difluoro-3-nitro-benzonitrile is used instead of 2 -Chloro-1,3-difluoro-4-nitro-benzene, and using THF instead of EtOH to obtain the title compound.

實施例248　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-(二氟甲基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 248 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methyl) Propyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile 209 (Steps 1 to 5) shall prevail, by using 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4- Nitro-benzene, and the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxane Penboran-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer- X to obtain the title compound.

實施例249　(S)-5-(5-(3-胺基吡咯啶-1-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用THF來代替EtOH，並使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 249 (S)-5-(5-(3-Aminopyrrolidine-1-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl) -6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile was synthesized in Example 209 (Step 1 ~5) shall prevail, by using 2,6-difluoro-3-nitro-benzonitrile instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and using THF instead of EtOH , And use the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl ((1S, 2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain Title compound.

實施例250　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-(二氟甲基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 250 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(difluoromethyl)-6 -Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- The synthesis of biphenyl]-4-carbonitrile is based on Example 209 (steps 1 to 5), and replaced by 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene 2-Chloro-1,3-difluoro-4-nitro-benzene, and the tertiary butyl N-[(3-内)-8-[3-(4-cyano) obtained in step 3 of Example 41 was used 3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-8 -Azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro -6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)- 7-Azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例251　5-(5-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用THF來代替EtOH，並使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 251 　 5-(5-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-4'-cyano-3'-fluoro-[ 1,1'-Biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole- The synthesis of 7-carbonitrile was based on Example 209 (steps 1 to 5), and 2,6-difluoro-3-nitro-benzonitrile was used instead of 2-chloro-1,3-difluoro- 4-nitro-benzene, and THF was used instead of EtOH, and the tertiary butyl N-[(3-内)-8-[3-(4-cyano-3- Fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-8-azabicyclo [3.2.1] Octan-3-yl] carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-aza Bicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例252　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-(二氟甲基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 252 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl) Yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1 ,1'-Biphenyl]-4-carbonitrile was synthesized according to Example 209 (steps 1 to 5), by using 2-(difluoromethyl)-1,3-difluoro-4-nitro -Benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and the tertiary butyl ((1S,2S,4R)-rel-7-( 4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1' -Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7- (4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1 '-Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例253　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用THF來代替EtOH，並使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 253 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3 ] The synthesis of triazole-7-carbonitrile is based on Example 209 (steps 1 to 5), by using 2,6-difluoro-3-nitro-benzonitrile instead of 2-chloro-1,3 -Difluoro-4-nitro-benzene, and use THF instead of EtOH, and use the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyanide) obtained in step 1 of Example 213 Group-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl] -3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'- Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl ]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例254　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用1,2,3-三氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 254``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-((1-Hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile-isomer-X was synthesized according to Example 209 (steps 1 to 5), by using 1,2,3-trifluoro-4-nitro-benzene instead of 2-chloro -1,3-Difluoro-4-nitro-benzene, and using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to obtain the title compound .

實施例255　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(6,7-二氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,2,3-三氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 255``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-((1-hydroxycyclobutyl)methyl)-1H -Benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 209 (Steps 1~5 ) Shall prevail, by using 1,2,3-trifluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene, using 1-(aminomethyl ) Cyclobutanol was used instead of 1-amino-2-methyl-propan-2-ol, and the tertiary butyl N-[(3S)-1-[3-(4 -Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) Pyrrolidin-3-yl) carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例256　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(6,7-二氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,2,3-三氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 256 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-( (1-Hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- The synthesis of carbonitrile is based on Example 209 (steps 1 to 5), by using 1,2,3-trifluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4- Nitro-benzene, using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and using the tertiary butyl obtained in step 3 of Example 41 N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-bis Oxolaboran-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl ((1S,2S, 4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound .

實施例257　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 257 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6- Fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-bi The synthesis of benzene]-4-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), by using 1-(aminomethyl)cyclobutanol instead of 1-amino-2 -Methyl-propan-2-ol to obtain the title compound.

實施例258　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-氯-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，且藉由使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 258 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)- The synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was carried out in Example 209 (Step 1~ 5) As the standard, by using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and by using the first step obtained in step 1 of Example 37 Tributyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4' -Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-linked Benzene]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例259　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-氯-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 259 　 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-6-fluoro-1- ((1-Hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4 -The synthesis of carbonitrile is based on Example 209 (steps 1 to 5), by using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, And using the tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5) obtained in step 3 of Example 41 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate Ester instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)amine Formate-isomer-X to obtain the title compound.

實施例260　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-(二氟甲基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 260 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl) Yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1 ,1'-Biphenyl]-4-carbonitrile-isomer-X was synthesized according to Example 209 (steps 1 to 5), by using 2-(difluoromethyl)-1,3-di Fluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and 1-(aminomethyl)cyclobutanol was used instead of 1-amino-2- Methyl-propan-2-ol to obtain the title compound.

實施例261　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-(二氟甲基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 261 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl) )Methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile 209 (Steps 1 to 5) shall prevail, by using 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4- Nitro-benzene, using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and using the tertiary butyl obtained in step 1 of Example 37 N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano -3'-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]- 3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例262　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-(二氟甲基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 262 "5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(difluoromethyl)-6 -Fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- The synthesis of biphenyl]-4-carbonitrile is based on Example 209 (steps 1 to 5), and replaced by 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene 2-chloro-1,3-difluoro-4-nitro-benzene, and use 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and Using the tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamic acid Ester instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)aminomethyl Ester-isomer-X to obtain the title compound.

實施例263　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-(二氟甲基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2-(二氟甲基)-1,3-二氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 263``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl) Yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1 ,1'-Biphenyl]-4-carbonitrile was synthesized according to Example 209 (steps 1 to 5), by using 2-(difluoromethyl)-1,3-difluoro-4-nitro -Benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propane-2 -Alcohol, and use the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5) obtained in step 1 of Example 213 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2. 1] Heptan-2-yl) carbamate-isomer-X to obtain the title compound.

實施例264　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-7-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 264 "5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3 ] The synthesis of triazole-7-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), and 2,6-difluoro-3-nitro-benzonitrile is used instead of 2 -Chloro-1,3-difluoro-4-nitro-benzene, and using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to obtain Title compound.

實施例265　(S)-5-(5-(3-胺基吡咯啶-1-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 265 "(S)-5-(5-(3-Aminopyrrolidine-1-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl) -6-Fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile was synthesized in Example 209 (Step 1 ~5), by using 2,6-difluoro-3-nitro-benzonitrile instead of 2-chloro-1,3-difluoro-4-nitro-benzene, using 1-(amino Methyl)cyclobutanol was used instead of 1-amino-2-methyl-propan-2-ol, and the tertiary butyl N-[(3S)-1-[3- (4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl Yl)pyrrolidin-3-yl)carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2 .1]Heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例266　5-(5-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 266 "5-(5-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-4'-cyano-3'-fluoro-[ 1,1'-Biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole- The synthesis of 7-carbonitrile was based on Example 209 (steps 1 to 5), and 2,6-difluoro-3-nitro-benzonitrile was used instead of 2-chloro-1,3-difluoro- 4-nitro-benzene, and use 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and use the third obtained in step 3 of Example 41 Butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxolpan-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl ((1S, 2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain Title compound.

實施例267　5-(5-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-4’-氰基-3’-氟-[1,1’-聯苯]-2-基)-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-7-甲腈之合成以實施例209(步驟1~5)為準，藉由使用2,6-二氟-3-硝基-苯甲腈來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 267 ``5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3' -Fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3 ] The synthesis of triazole-7-carbonitrile is based on Example 209 (steps 1 to 5), by using 2,6-difluoro-3-nitro-benzonitrile instead of 2-chloro-1,3 -Difluoro-4-nitro-benzene, using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and using the result obtained in step 1 of Example 213 The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate Instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamic acid Ester-isomer-X to obtain the title compound.

實施例268　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,2,3-三氟-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 268 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro -1-((1-Hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl ]-4-carbonitrile was synthesized in accordance with Example 209 (steps 1 to 5), by using 1,2,3-trifluoro-4-nitro-benzene instead of 2-chloro-1,3-di Fluoro-4-nitro-benzene, using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and using the first step obtained in step 1 of Example 213 Tributyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead Tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate- Isomer-X to give the title compound.

實施例269　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-氯-6-氟-1-((1-羥基環丁基)甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，且使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 269 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6- Fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-bi The synthesis of benzene]-4-carbonitrile was based on Example 209 (steps 1 to 5), by using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propane- 2-alcohol, and the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2. 1) Heptan-2-yl) carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2 .1]Heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例270　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-((1-羥基環丁基)甲基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈-異構物-X之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 270 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-((1-hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- The synthesis of biphenyl]-4-carbonitrile-isomer-X is based on Example 209 (steps 1 to 5), by using 1,3-difluoro-2-methyl-4-nitro-benzene Instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and use 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol , And get the title compound.

實施例271　(S)-5’-(3-胺基吡咯啶-1-羰基)-3-氟-2’-(6-氟-1-((1-羥基環丁基)甲基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 271 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-((1-hydroxycyclobutyl)methyl)- 7-Methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 209 (Step 1 ~5) shall prevail. By using 1,3-difluoro-2-methyl-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene, use 1- (Aminomethyl)cyclobutanol was substituted for 1-amino-2-methyl-propan-2-ol, and the tertiary butyl N-[(3S)-1- obtained in step 1 of Example 37 was used. [3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-aza Bicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例272　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-3-氟-2’-(6-氟-1-((1-羥基環丁基)甲基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 272 "5'-((3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'-(6-fluoro-1- ((1-Hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]- The synthesis of 4-carbonitrile was based on Example 209 (steps 1 to 5), and 1,3-difluoro-2-methyl-4-nitro-benzene was used instead of 2-chloro-1,3- Difluoro-4-nitro-benzene, using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and using the product obtained in step 3 of Example 41 Tertiary butyl N-[(3-内)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3 ,2-Dioxolaboran-2-yl)benzyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl (( 1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxole Alk-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X, The title compound is obtained.

實施例273　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成(步驟1)將2-溴-1,3-二氟-4-硝基-苯 3g溶解於THF 31.5mL中並添加TEA 2.6mL、1-胺基-2-甲基-丙烷-2-醇 1.4mL，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(2-溴-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。Example 273 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked Synthesis of benzene]-4-carbonitrile-isomer-X (Step 1) Dissolve 3g of 2-bromo-1,3-difluoro-4-nitro-benzene in 31.5mL of THF and add 2.6mL of TEA, 1.4 mL of 1-amino-2-methyl-propan-2-ol was stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propane -2-ol.

(步驟2)將前述步驟1所得到的1-(2-溴-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.03g溶解於乙酸 6.7mL中。於室溫添加N-碘琥珀醯亞胺 981mg，於50℃攪拌3小時。添加MTBE、水，並以MTBE萃取2次。以無水硫酸鈉乾燥合起來的有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(2-溴-3-氟-4-碘-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。(Step 2) Dissolve 1.03 g of 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 1 above in 6.7 mL of acetic acid. 981 mg of N-iodosuccinimide was added at room temperature, and the mixture was stirred at 50°C for 3 hours. Add MTBE, water, and extract twice with MTBE. After drying the combined organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-bromo-3-fluoro-4-iodo-6-nitro-anilino)-2- Methyl-propan-2-ol.

(步驟3)　將前述步驟2所得到的1-(2-溴-3-氟-4-碘-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.33g及鐵1.33g溶解於THF 10.2mL、2當量濃度鹽酸 10.2mL中，於60℃攪拌1小時。添加MTBE，進行矽藻土過濾。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(6-胺基-2-溴-3-氟-4-碘-苯胺基)-2-甲基-丙烷-2-醇。(Step 3) ``The 1-(2-bromo-3-fluoro-4-iodo-6-nitro-anilino)-2-methyl-propane-2-ol 1.33g and iron 1.33 obtained in the aforementioned step 2 g was dissolved in 10.2 mL of THF and 10.2 mL of 2 equivalent hydrochloric acid, and stirred at 60°C for 1 hour. Add MTBE and filter with diatomaceous earth. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2- Methyl-propan-2-ol.

(步驟4)將前述步驟3所得到的1-(6-胺基-2-溴-3-氟-4-碘-苯胺基)-2-甲基-丙烷-2-醇 940mg溶解於水1.88mL、THF 4.7mL中。於0℃添加12當量濃度鹽酸2.82mL，滴下添加亞硝酸鈉水溶液(使亞硝酸鈉209mg溶解於水0.63mL而成者)，於室溫攪拌1小時。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(7-溴-6-氟-5-碘-苯并三唑-1-基)-2-甲基-丙烷-2-醇。(Step 4) Dissolve 940 mg of 1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2-methyl-propan-2-ol obtained in step 3 above in water 1.88 mL, THF 4.7mL. 2.82 mL of 12 equivalents of hydrochloric acid was added at 0°C, an aqueous sodium nitrite solution (dissolved 209 mg of sodium nitrite in 0.63 mL of water) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(7-bromo-6-fluoro-5-iodo-benzotriazol-1-yl)-2 -Methyl-propan-2-ol.

(步驟5)將實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 50mg、前述步驟4所得到的1-(7-溴-6-氟-5-碘-苯并三唑-1-基)-2-甲基-丙烷-2-醇 47.9mg懸浮於1,4-二噁烷0.3mL中。於室溫添加Pd(dba)2 4.1mg、X-phos 6.8mg、磷酸三鉀56.7mg，進行氮取代，於90℃徹夜攪拌。添加乙酸乙酯，裝入NH矽膠中，並以乙酸乙酯：甲醇＝10：1洗淨。蒸餾去除溶劑，對殘渣添加乙腈 1.0mL、4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL並攪拌10分鐘。蒸餾去除溶劑，將殘渣溶解於DMSO中，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 5) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5) obtained in step 2 of Example 207 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl) carbamate-isomer-X 50mg, 1-(7-bromo-6-fluoro-5-iodo-benzotriazol-1-yl) obtained in step 4 above 47.9 mg of -2-methyl-propan-2-ol was suspended in 0.3 mL of 1,4-dioxane. Pd(dba) 2 4.1 mg, X-phos 6.8 mg, and tripotassium phosphate 56.7 mg were added at room temperature, nitrogen substitution was performed, and the mixture was stirred at 90°C overnight. Add ethyl acetate, put it into NH silica gel, and wash with ethyl acetate: methanol = 10:1. The solvent was distilled off, 1.0 mL of acetonitrile and 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 10 minutes. The solvent was distilled off, the residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例274　(S)-5’-(3-胺基吡咯啶-1-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例273(步驟1~5)為準，藉由使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 274 ``(S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)- The synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was carried out in Example 273 (Step 1~ 5) shall prevail, by using the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate instead of tertiary butyl Group ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer -X to obtain the title compound.

實施例275　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例273(步驟1~5)為準，藉由使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 275 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-bromo-6-fluoro-1- (2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4 -The synthesis of formonitrile is based on Example 273 (steps 1 to 5), by using the tertiary butyl N-[(3-内)-8-[3-(4- Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)- 8-azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl((1S,2S,4R)-rel-7-(4'-cyano-3'- Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl) -7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例276　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-3-氟-2’-(6-氟-1-((1-羥基環丁基)甲基)-7-甲基-1H-苯并[d][1,2,3]三唑-5-基)-[1,1’-聯苯]-4-甲腈之合成以實施例209(步驟1~5)為準，藉由使用1,3-二氟-2-甲基-4-硝基-苯來代替2-氯-1,3-二氟-4-硝基-苯，使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，並使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 276 "5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6- Fluoro-1-((1-hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- The synthesis of biphenyl]-4-carbonitrile was based on Example 209 (steps 1 to 5), by using 1,3-difluoro-2-methyl-4-nitro-benzene instead of 2-chloro- 1,3-Difluoro-4-nitro-benzene, use 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol, and use the procedure in Example 213 1 The obtained tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)amine Formate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl) Carbamate-isomer-X to give the title compound.

實施例277　5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例273(步驟1~5)為準，藉由使用實施例213步驟1所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，而得到標題化合物。Example 277 ``5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6- Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-linked The synthesis of benzene]-4-carbonitrile was based on Example 273 (Steps 1 to 5). By using the tertiary butyl ((1S,2S,4R)-rel-7- (4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1 '-Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate instead of tertiary butyl((1S,2S,4R)-rel-7 -(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1, 1'-Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例278　5’-((1R,2R,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-環丙基-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成　(步驟1)將實施例273步驟1所得到的1-(2-溴-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 975mg溶解於1,4-二噁烷 10.6 mL中。於室溫下，添加二氯雙(三環己基膦)鈀(II)234mg、環丙基硼酸464mg、磷酸三鉀2.02g，於10℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-((2-環丙基-3-氟-6-硝基苯基)胺基)-2-甲基丙烷-2-醇。Example 278 ``5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-cyclopropyl- 6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1' -Biphenyl]-4-carbonitrile synthesis (step 1) The 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propane obtained in step 1 of Example 273 975 mg of -2-ol was dissolved in 10.6 mL of 1,4-dioxane. At room temperature, 234 mg of dichlorobis(tricyclohexylphosphine)palladium(II), 464 mg of cyclopropylboronic acid, and 2.02 g of tripotassium phosphate were added, followed by stirring at 10°C overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((2-cyclopropyl-3-fluoro-6-nitrophenyl)amine Yl)-2-methylpropan-2-ol.

(步驟2)將前述步驟1所得到的1-((2-環丙基-3-氟-6-硝基苯基)胺基)-2-甲基丙烷-2-醇 204mg溶解於乙腈 1.5mL中。於室溫添加NBS 196mg，並於50℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-((4-溴-2-環丙基-3-氟-6-硝基苯基)胺基)-2-甲基丙烷-2-醇。(Step 2) Dissolve 204 mg of 1-((2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropane-2-ol obtained in step 1 above in acetonitrile 1.5 mL in. 196 mg of NBS was added at room temperature, and stirred at 50°C for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((4-bromo-2-cyclopropyl-3-fluoro-6-nitro Phenyl)amino)-2-methylpropan-2-ol.

(步驟3)將前述步驟2所得到的1-((4-溴-2-環丙基-3-氟-6-硝基苯基)胺基)-2-甲基丙烷-2-醇 250mg、鐵250mg溶解於THF 2.4mL、2當量濃度鹽酸 2.4mL中，於60℃攪拌1小時。添加乙酸乙酯，進行矽藻土過濾。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-((6-胺基-4-溴-2-環丙基-3-氟苯基)胺基)-2-甲基丙烷-2-醇。(Step 3) 250 mg of 1-((4-bromo-2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropan-2-ol obtained in step 2 above , 250mg of iron was dissolved in 2.4mL of THF, 2.4mL of 2N hydrochloric acid, and stirred at 60°C for 1 hour. Add ethyl acetate and perform Celite filtration. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((6-amino-4-bromo-2-cyclopropyl-3-fluorophenyl)amine Yl)-2-methylpropan-2-ol.

(步驟4)將前述步驟3所得到的1-((6-胺基-4-溴-2-環丙基-3-氟苯基)胺基)-2-甲基丙烷-2-醇 192mg溶解於THF 2.0mL、2當量濃度鹽酸水溶液 2.0mL中。滴下添加亞硝酸鈉水溶液(使亞硝酸鈉54mg溶解於水0.16mL而成者)，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-7-環丙基-6-氟-1H-苯并[d][1,2,3]三唑-1-基)-　2-甲基丙烷-2-醇。(Step 4) 192 mg of 1-((6-amino-4-bromo-2-cyclopropyl-3-fluorophenyl)amino)-2-methylpropan-2-ol obtained in step 3 above Dissolved in 2.0 mL of THF, 2.0 mL of 2 equivalent hydrochloric acid aqueous solution. A sodium nitrite aqueous solution (54 mg of sodium nitrite was dissolved in 0.16 mL of water) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-7-cyclopropyl-6-fluoro-1H-benzo[d][1 ,2,3]Triazol-1-yl)-"2-methylpropan-2-ol.

(步驟5)將實施例213步驟1所得到的第三丁基((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯 15mg、前述步驟4所得到的1-(5-溴-7-環丙基-6-氟-1H-苯并[d][1,2,3]三唑-1-基)-　2-甲基丙烷-2-醇 10.5mg溶解於1,4-二噁烷0.2mL中。添加Pd(dba)2 1.2mg、X-phos 2.0mg、磷酸三鉀17mg，進行氮取代，於100℃徹夜攪拌。添加乙酸乙酯，裝入NH矽膠中，並以乙酸乙酯：甲醇＝10：1洗淨。蒸餾去除溶劑，對殘渣添加乙腈 1.0mL、4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL並攪拌10分鐘。蒸餾去除溶劑，將殘渣溶解於DMSO中，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 5) The tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5) obtained in step 1 of Example 213 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 ]Heptan-2-yl)carbamate 15mg, 1-(5-bromo-7-cyclopropyl-6-fluoro-1H-benzo[d][1,2,3 obtained in step 4 above ] Triazol-1-yl)-2-methylpropan-2-ol 10.5 mg was dissolved in 0.2 mL of 1,4-dioxane. Pd(dba) 2 1.2 mg, X-phos 2.0 mg, and tripotassium phosphate 17 mg were added, nitrogen substitution was performed, and the mixture was stirred overnight at 100°C. Add ethyl acetate, put it into NH silica gel, and wash with ethyl acetate: methanol = 10:1. The solvent was distilled off, 1.0 mL of acetonitrile and 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution were added to the residue, and the mixture was stirred for 10 minutes. The solvent was distilled off, the residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例279　5’-((1R,2R,4S)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-環丙基-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X之合成Example 279 ``5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-cyclopropyl- 6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1' -Biphenyl]-4-carbonitrile-isomer-X synthesis

以實施例278(步驟1~5)為準，藉由使用實施例207步驟2所得到的第三丁基　((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X來代替第三丁基((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯，而得到標題化合物。Taking Example 278 (Steps 1 to 5) as the standard, by using the tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' obtained in step 2 of Example 207) -Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl )-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X instead of tertiary butyl((1S,2S,4R)-rel-7-(4 '-Cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'- Biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate to obtain the title compound.

實施例280　(S)-5’-(3-胺基吡咯啶-1-羰基)-　2’-(7-環丙基-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例278(步驟1~5)為準，藉由使用實施例37步驟1所得到的第三丁基　N-[(3S)-1-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]　吡咯啶-3-基]　胺甲酸酯來代替第三丁基((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯，而得到標題化合物。Example 280 "(S)-5'-(3-aminopyrrolidine-1-carbonyl)-"2'-(7-cyclopropyl-6-fluoro-1-(2-hydroxy-2-methylpropyl) )-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile was synthesized in Example 278 (Step 1~5), by using the tertiary butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4- obtained in step 1 of Example 37 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) ``pyrrolidin-3-yl)'' carbamate instead of Tributyl((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate, and The title compound is obtained.

實施例281　5’-((3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基)-2’-(7-環丙基-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈之合成以實施例278(步驟1~5)為準，藉由使用實施例41步驟3所得到的第三丁基　N-[(3-內)-8-[3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基1,3,2-二氧雜環戊硼烷-2-基)苯甲醯基]-8-氮雜雙環[3.2.1]辛烷-3-基]胺甲酸酯來代替第三丁基((1S,2S,4R)-rel-7-(4’-氰基-3’-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-[1,1’-聯苯]-3-羰基)-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯，而得到標題化合物。Example 281 ``5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-cyclopropyl-6-fluoro- 1-(2-Hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl] The synthesis of -4-carbonitrile is based on Example 278 (Steps 1 to 5), by using the tertiary butyl N-[(3-内)-8-[3-( 4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzyl) -8-Azabicyclo[3.2.1]octan-3-yl]carbamate instead of tertiary butyl ((1S,2S,4R)-rel-7-(4'-cyano-3' -Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl )-7-azabicyclo[2.2.1]heptan-2-yl)carbamate to obtain the title compound.

實施例282　(S)-5'-((3-胺基吡咯啶-1-基)甲基)-4''-甲基-[1,1'：2,1''-聯三苯]-4-甲腈之合成(步驟1)使3-溴-4-氯-苯甲醛　100mg、第三丁基N-[(3S)-吡咯啶-3-基]胺甲酸酯　93.4mg溶解於MeOH　1.0mL中。在0℃添加乙酸 0.1mL、硼烷-2-甲基吡啶(picoline)錯合物 146mg，並在室溫下攪拌一晚。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[(3-溴-4-氯-苯基)甲基]吡咯啶-3-基]胺甲酸酯。Example 282 "(S)-5'-((3-Aminopyrrolidin-1-yl)methyl)-4"-methyl-[1,1': 2,1''-terphenyl] Synthesis of -4-carbonitrile (Step 1) Dissolve 100 mg of 3-bromo-4-chloro-benzaldehyde and 93.4 mg of tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate in MeOH 　 1.0mL. 0.1 mL of acetic acid and 146 mg of borane-2-picoline complex were added at 0°C, and the mixture was stirred at room temperature overnight. Add ethyl acetate, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[(3-bromo-4-chloro-phenyl) Methyl]pyrrolidin-3-yl]carbamate.

(步驟2)使以前述步驟1獲得之第三丁基　N-[(3S)-1-[(3-溴-4-氯-苯基)甲基]吡咯啶-3-基]胺甲酸酯　60mg、(4-氰基苯基)硼酸 24.9mg溶解於1,4-二噁烷 0.77mL中。於室溫添加PdCl2(dppf)CH2 Cl2 3.4mg、磷酸三鉀 97.9mg，並於125℃攪拌45分鐘。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[[4-氯-3-(4-氰基苯基)苯基]甲基]吡咯啶-3-基]胺甲酸酯。(Step 2) Make the tertiary butyl N-[(3S)-1-[(3-bromo-4-chloro-phenyl)methyl]pyrrolidin-3-yl]carbamic acid obtained in step 1 above 60 mg of ester and 24.9 mg of (4-cyanophenyl)boronic acid were dissolved in 0.77 mL of 1,4-dioxane. At room temperature, 3.4 mg of PdCl2(dppf)CH 2 Cl 2 and 97.9 mg of tripotassium phosphate were added, and the mixture was stirred at 125°C for 45 minutes. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[[4-chloro-3-(4-cyano Phenyl)phenyl]methyl]pyrrolidin-3-yl]carbamate.

(步驟3)使以前述步驟2獲得之第三丁基 N-[(3S)-1-[[4-氯-3-(4-氰基苯基)苯基]甲基]吡咯啶-3-基]胺甲酸酯 20mg、對甲苯基硼酸　13.2mg、Pd2 (dba)3 2.23mg、磷酸三鉀　20.6mg、及1M　PCy3 THF溶液　0.1mL懸浮於1,4-二噁烷 0.5mL中，並在160℃下攪拌45分鐘。以NH矽膠過濾反應液，蒸餾去除濾液之溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基　N-[(3S)-1-[[3-(4-氰基苯基)-4-(對甲苯基)苯基]甲基]吡咯啶-3-基]胺甲酸酯。(Step 3) Make the tertiary butyl N-[(3S)-1-[[4-chloro-3-(4-cyanophenyl)phenyl]methyl]pyrrolidine-3 obtained in the aforementioned step 2 -Base) carbamate 20mg, p-tolyl boronic acid 13.2mg, Pd 2 (dba) 3 2.23mg, tripotassium phosphate 20.6mg, and 1M PCy 3 THF solution 0.1mL suspended in 1,4-dioxane 0.5mL And stir at 160°C for 45 minutes. The reaction solution was filtered with NH silica gel, and the solvent of the filtrate was removed by distillation. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(3S)-1-[[3-(4-cyanophenyl)- 4-(p-tolyl)phenyl]methyl]pyrrolidin-3-yl]carbamate.

(步驟4)使前述步驟3所得到的第三丁基　N-[(3S)-1-[[3-(4-氰基苯基)-4-(對甲苯基)苯基]甲基]吡咯啶-3-基]胺甲酸酯 10mg溶解於TFA 0.3mL中，以LCMS確認到反應的進行之後進行減壓濃縮。以逆相HPLC(移動相：水/乙腈)純化殘渣，藉此得到標題化合物。(Step 4) Make the tertiary butyl N-[(3S)-1-[[3-(4-cyanophenyl)-4-(p-tolyl)phenyl]methyl] obtained in the aforementioned step 3 10 mg of pyrrolidin-3-yl] carbamate was dissolved in 0.3 mL of TFA, and the progress of the reaction was confirmed by LCMS, followed by concentration under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例283　5'-(((1S，2S，4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'',3-二氟-4''-甲基-[1,1'：2',1''-聯三苯]-4-甲腈-異構物-X之合成　(步驟1)將3-溴-4-氯-苯甲醛 1.1g溶解於1,4-二噁烷 13mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸 870mg、PdCl2 (dppf)CH2 Cl2 110mg、2M碳酸鈉水溶液　6.3mL，並於90℃攪拌5小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-(2-氯-5-甲醯基-苯基)-2-氟-苯甲腈。Example 283 5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'',3- Synthesis of difluoro-4''-methyl-[1,1': 2',1''-terphenyl]-4-carbonitrile-isomer-X (step 1) -1.1 g of chloro-benzaldehyde was dissolved in 13 mL of 1,4-dioxane. 870 mg of (4-cyano-3-fluoro-phenyl)boronic acid, 110 mg of PdCl 2 (dppf)CH 2 Cl 2 and 6.3 mL of 2M sodium carbonate aqueous solution were added at room temperature, and the mixture was stirred at 90°C for 5 hours. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-(2-chloro-5-methanyl-phenyl)-2-fluoro-benzonitrile.

(步驟2)將以前述步驟1獲得之4-(2-氯-5-甲醯基-苯基)-2-氟-苯甲腈 505mg溶解於1,4-二噁烷　19.45mL中。於室溫下添加(2-氟-4-甲基-苯基)硼酸 599mg、Pd2 dba3 89mg、1M PCy3 THF溶液 0.1mL、磷酸三鉀　1.24g，並在微波反應裝置中於160℃攪拌1小時。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到2-氟-4-[2-(2-氟-4-甲基-苯基)-5-甲醯基-苯基]苯甲腈。(Step 2) 505 mg of 4-(2-chloro-5-methanyl-phenyl)-2-fluoro-benzonitrile obtained in step 1 above was dissolved in 19.45 mL of 1,4-dioxane. At room temperature, 599 mg of (2-fluoro-4-methyl-phenyl) boric acid, 89 mg of Pd 2 dba 3 , 0.1 mL of 1M PCy 3 THF solution, and 1.24 g of tripotassium phosphate were added, and the mixture was heated at 160°C in a microwave reaction device. Stir for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 2-fluoro-4-[2-(2-fluoro-4-methyl-phenyl) -5-methanyl-phenyl]benzonitrile.

(步驟3)使以前述步驟2獲得之2-氟-4-[2-(2-氟-4-甲基-苯基)-5-甲醯基-苯基]苯甲腈 10mg溶解於DCM 0.6mL中。於室溫添加以實施例202(步驟2)合成之第三丁基 ((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 9.55mg、三乙醯氧基硼氫化鈉 25.4mg，並於室溫攪拌1小時。蒸餾去除溶劑，添加氯仿，過濾不溶物。蒸餾去除溶劑，添加乙腈 0.2mL、4當量濃度鹽酸-1,4-二噁烷溶液 0.2mL，攪拌10分鐘。添加DMSO 0.6mL，以逆相HPLC(移動相：水/乙腈)純化，藉此得到標題化合物。(Step 3) Dissolve 10 mg of 2-fluoro-4-[2-(2-fluoro-4-methyl-phenyl)-5-methanyl-phenyl]benzonitrile obtained in step 2 above in DCM 0.6mL. Add the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate synthesized in Example 202 (Step 2) at room temperature -Isomer-X 9.55 mg, sodium triacetoxyborohydride 25.4 mg, and stirred at room temperature for 1 hour. The solvent was distilled off, chloroform was added, and the insoluble matter was filtered. The solvent was distilled off, 0.2 mL of acetonitrile and 0.2 mL of 4-eq hydrochloric acid-1,4-dioxane solution were added, and stirred for 10 minutes. 0.6 mL of DMSO was added and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

實施例284　(S)-5'-((3-胺基-3-甲基吡咯啶-1-基)甲基)-2'',3-二氟-4''-甲基-[1,1'：2',1''-聯三苯]-4-甲腈之合成以實施例283(步驟3)為準，使用第三丁基 (S)-(3-甲基吡咯啶-3-基)胺甲酸酯來取代第三丁基 ((1S，2S，4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，藉此獲得標題化合物。Example 284 ``(S)-5'-((3-amino-3-methylpyrrolidin-1-yl)methyl)-2'',3-difluoro-4''-methyl-[1 ,1': 2',1''-terphenyl]-4-carbonitrile was synthesized in accordance with Example 283 (step 3), using tertiary butyl (S)-(3-methylpyrrolidine- 3-yl) carbamate instead of tertiary butyl ((1S, 2S, 4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl) carbamate-isomer -X, thereby obtaining the title compound.

實施例285　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1，1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成　(步驟1)將3-溴-4-氯-苯甲酸 19g溶解於DMF 160mL中。於25℃添加DMAP 20g、WSC・HCl 31g，接著添加t-BuOH 38mL並於室溫徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基 3-溴-4-氯-苯甲酸酯。Example 285 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(6, 7-Difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1 Synthesis of'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride (Step 1) Dissolve 19 g of 3-bromo-4-chloro-benzoic acid in 160 mL of DMF. 20 g of DMAP and 31 g of WSC·HCl were added at 25°C, and then 38 mL of t-BuOH was added, and the mixture was stirred at room temperature overnight. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-bromo-4-chloro-benzoic acid ester.

(步驟2)將前述步驟1所得到的第三丁基　3-溴-4-氯-苯甲酸酯 1.00g溶解於1,4-二噁烷 8.6mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸509mg、Pd(PPh3 )4 119mg、2M碳酸鈉水溶液 4.3mL，在微波反應裝置中於120℃攪拌反應液30分鐘。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基 4-氯-3-(4-氰基-3-氟-苯基)苯甲酸酯。(Step 2) Dissolve 1.00 g of the tertiary butyl 3-bromo-4-chloro-benzoic acid ester obtained in the aforementioned step 1 in 8.6 mL of 1,4-dioxane. 509 mg of (4-cyano-3-fluoro-phenyl)boronic acid, 119 mg of Pd(PPh 3 ) 4 and 4.3 mL of 2M sodium carbonate aqueous solution were added at room temperature, and the reaction solution was stirred at 120° C. for 30 minutes in a microwave reactor. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoic acid ester.

(步驟3)將前述步驟2所得到的第三丁基 4-氯-3-(4-氰基-3-氟-苯基)苯甲酸酯 300mg溶解於1,4-二噁烷5mL中。於室溫添加Pd(OAc)2 40mg、KOAc 300mg、雙品納可基二硼烷 500mg、Silica-SMAP 50mg，於100℃攪拌26小時。過濾反應液，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基 3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯。(Step 3) Dissolve 300 mg of tertiary butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoate obtained in step 2 above in 5 mL of 1,4-dioxane . 40 mg of Pd(OAc) 2 , 300 mg of KOAc, 500 mg of dipinacyl diborane, and 50 mg of Silica-SMAP were added at room temperature, and the mixture was stirred at 100°C for 26 hours. The reaction liquid was filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4) ,5,5-Tetramethyl-1,3,2-dioxole-2-yl)benzoate.

(步驟4)將1,2,3-三氟-4-硝基-苯 500mg、1-胺基-2-甲基-丙烷-2-醇 302mg、三乙基胺 0.590mL溶解於THF 5.65mL中，並在45℃攪拌5小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。(Step 4) Dissolve 500 mg of 1,2,3-trifluoro-4-nitro-benzene, 302 mg of 1-amino-2-methyl-propan-2-ol, and 0.590 mL of triethylamine in 5.65 mL of THF And stir at 45°C for 5 hours. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propane- 2-alcohol.

(步驟5)將前述步驟4所得到的1-(2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 74.1g溶解於DMF 602mL中。於室溫添加NBS 64.3g，並於90 ℃攪拌1小時。添加乙酸乙酯，並以水洗淨3次。接著以飽和食鹽水洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以IPE：己烷＝1：1進行結晶化，並將結晶以己烷洗淨2次。將獲得之結晶乾燥，藉此獲得1-(4-溴-2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。(Step 5) Dissolve 74.1 g of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in Step 4 above in 602 mL of DMF. NBS 64.3g was added at room temperature, and it stirred at 90 degreeC for 1 hour. Add ethyl acetate and wash with water 3 times. Then it was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. Crystallization was performed with IPE:hexane=1:1, and the crystals were washed twice with hexane. The obtained crystals are dried, thereby obtaining 1-(4-bromo-2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

(步驟6)將以前述步驟5獲得之1-(4-溴-2,3-二氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 82.2g、氯化銨　82.2g、鐵粉 41.1g懸浮於EtOH 421mL、水　421mL中，並在60 ℃徹夜攪拌。添加MTBE，進行矽藻土過濾。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑，藉此得到1-(6-胺基-4-溴-2,3-二氟-苯胺基)-2-甲基-丙烷-2-醇。(Step 6) 82.2g of 1-(4-bromo-2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 5 above, ammonium chloride 82.2 g and 41.1 g of iron powder were suspended in 421 mL of EtOH and 421 mL of water, and stirred overnight at 60°C. Add MTBE and filter with diatomaceous earth. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 1-(6-amino-4-bromo-2,3-difluoro-anilino)- 2-Methyl-propan-2-ol.

(步驟7)將前述步驟6所得到的1-(6-胺基-4-溴-2,3-二氟-苯胺基)-2-甲基-丙烷-2-醇 68.1g溶解於水 136mL、THF 341mL中。於0℃以3分鐘滴下添加12當量濃度鹽酸204mL，亞硝酸鈉(使亞硝酸鈉20.7g溶解而成的水溶液60mL)，於室溫攪拌1小時。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。對殘渣添加IPE：己烷＝1：1 68mL，並濾取產生之固體，且以IPE：己烷＝1：1洗淨。使獲得之固體乾燥，獲得1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇。(Step 7) Dissolve 68.1 g of 1-(6-amino-4-bromo-2,3-difluoro-anilino)-2-methyl-propan-2-ol obtained in step 6 above in 136 mL of water , THF 341mL. 204 mL of 12-eq hydrochloric acid and sodium nitrite (60 mL of an aqueous solution obtained by dissolving 20.7 g of sodium nitrite) were added dropwise at 0°C for 3 minutes, and the mixture was stirred at room temperature for 1 hour. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. To the residue, 68 mL of IPE:hexane=1:1 was added, and the resulting solid was filtered out, and washed with IPE:hexane=1:1. The obtained solid is dried to obtain 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol.

(步驟8)將前述步驟3所得到的第三丁基 3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 3.2g、及前述步驟7所得到的1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇 3.01g溶解於1,4-二噁烷25.2mL中。於室溫下添加Pd(dba)2 348mg、X-Phos 577mg、磷酸三鉀 4.81g，於100℃徹夜攪拌。蒸餾去除溶劑，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於THF 15.0mL中。於0℃添加12當量濃度鹽酸 15.0mL，於室溫攪拌2小時。添加MTBE，並以水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑，藉此得到3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸。(Step 8) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3, 3.2 g of 2-dioxoleborolan-2-yl) benzoate and the 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl obtained in step 7) ) 3.01 g of 2-methyl-propane-2-ol was dissolved in 25.2 mL of 1,4-dioxane. Pd(dba) 2 348 mg, X-Phos 577 mg, and 4.81 g of tripotassium phosphate were added at room temperature, and the mixture was stirred at 100°C overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 15.0 mL of THF. 15.0 mL of 12 equivalents of hydrochloric acid was added at 0°C, and stirred at room temperature for 2 hours. Add MTBE, wash with water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1 -(2-Hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid.

(步驟9)將以前述步驟8獲得之3-(4-氰基-3-氟-苯基)-4-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]苯甲酸 120mg溶解於THF 1.29mL中。於室溫添加WSC・HCl 98.6mg、HOBt 78.8mg，並在室溫下攪拌20分鐘。添加硼氫化鈉 19.5mg，攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：氯仿/甲醇)純化殘渣，藉此得到4-[2-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-(羥甲基)苯基]-2-氟-苯甲腈。(Step 9) The 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propane) obtained in the aforementioned step 8 (Yl)benzotriazol-5-yl]benzoic acid 120 mg was dissolved in 1.29 mL of THF. 98.6 mg of WSC·HCl and 78.8 mg of HOBt were added at room temperature, and the mixture was stirred at room temperature for 20 minutes. 19.5 mg of sodium borohydride was added, and the mixture was stirred for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 4-[2-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzene Triazol-5-yl]-5-(hydroxymethyl)phenyl]-2-fluoro-benzonitrile.

(步驟10)使以前述步驟9獲得之4-[2-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-(羥甲基)苯基]-2-氟-苯甲腈 100mg溶解於DCM 2.21mL中。於室溫添加DESS-MARTIN過碘烷 103mg，並於室溫撤夜攪拌。減壓濃縮反應液、以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-[2-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-甲醯基-苯基]-2-氟-苯甲腈。(Step 10) Make the 4-[2-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]-5 obtained in the aforementioned step 9 100 mg of -(hydroxymethyl)phenyl]-2-fluoro-benzonitrile was dissolved in 2.21 mL of DCM. 103 mg of DESS-MARTIN periodinane was added at room temperature, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-[2-[6,7-difluoro-1-(2-hydroxy- 2-Methyl-propyl)benzotriazol-5-yl]-5-methanyl-phenyl]-2-fluoro-benzonitrile.

(步驟11)使以前述步驟10獲得之4-[2-[6,7-二氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-甲醯基-苯基]-2-氟-苯甲腈 50mg溶解於DCM 1.11mL中。於室溫添加以實施例202(步驟2)合成之第三丁基 ((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X　47.1mg，並於室溫攪拌30分鐘。於室溫添加三乙醯氧基硼氫化鈉 94.1mg，並於室溫下撤夜攪拌。添加氯仿，濾別不溶物，並蒸餾去除溶劑。以矽膠管柱層析法(NH矽膠，移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於MeOH 1.0mL中，添加4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL，並攪拌30分鐘。將反應液之溶劑蒸餾去除，藉此得到標題化合物。(Step 11) Make the 4-[2-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]-5 obtained in the aforementioned step 10 50 mg of -methanyl-phenyl]-2-fluoro-benzonitrile was dissolved in 1.11 mL of DCM. Add the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate synthesized in Example 202 (Step 2) at room temperature -Isomer-X" 47.1 mg, and stirred at room temperature for 30 minutes. 94.1 mg of sodium triacetoxyborohydride was added at room temperature, and the mixture was stirred overnight at room temperature. Add chloroform, filter out the insoluble matter, and distill to remove the solvent. The residue was purified by silica gel column chromatography (NH silica gel, mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 1.0 mL of MeOH, 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred for 30 minutes. The solvent of the reaction liquid was distilled off to obtain the title compound.

實施例286　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(7-氯-6-氟-1-((1-羥基環丁基）甲基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成以實施例285(步驟4~11)為準，藉由使用2-氯-1,3-二氟-4-硝基-苯來代替1,2,3-三氟-4-硝基-苯，且使用1-(胺基甲基)環丁醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 286 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(7- Chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1, The synthesis of 1'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride is based on Example 285 (steps 4 to 11), by using 2-chloro-1,3-difluoro- 4-nitro-benzene instead of 1,2,3-trifluoro-4-nitro-benzene, and 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propane -2-ol to obtain the title compound.

實施例287　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-3-氟-2'-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲唑-5-基)-[1,1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成(步驟1)使5-溴-6-氟-1H-吲唑 94mg溶解於DMF 1.5mL中。於室溫添加碳酸銫　285mg、2,2-二甲基環氧乙烷 0.078mL，於90℃攪拌16小時。以飽和氯化銨水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇。Example 287 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-3-fluoro-2' -(6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer- Synthesis of X 2 Hydrochloride (Step 1) Dissolve 94 mg of 5-bromo-6-fluoro-1H-indazole in 1.5 mL of DMF. 285 mg of cesium carbonate and 0.078 mL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 90°C for 16 hours. It was quenched with saturated ammonium chloride aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propane- 2-alcohol.

(步驟2)以實施例285(步驟8~11)為準，藉由使用前述步驟1所得到的1-(5-溴-6-氟-吲唑-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 285 (Steps 8 to 11), by using the 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl- Propane-2-ol was substituted for 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol to obtain the title compound.

實施例288　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(7-氯-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1，1'-聯苯]-4-甲腈 -異構物-X 2鹽酸鹽之合成以實施例285(步驟4~11)為準，藉由使用2-氯-1,3-二氟-4-硝基-苯來代替1,2,3-三氟-4-硝基-苯，且使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 288 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(7- Chloro-1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1, The synthesis of 1'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride is based on Example 285 (steps 4 to 11), by using 2-chloro-1,3-difluoro- 4-nitro-benzene is used instead of 1,2,3-trifluoro-4-nitro-benzene, and 3-(aminomethyl)pentane-3-ol is used instead of 1-amino-2-methyl Yl-propan-2-ol to obtain the title compound.

實施例289　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-3-氟-2'-(6-氟-1-(2-羥基-2-甲基丙基)-1H-吲哚-5-基)-[1,1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成　(步驟1)使5-溴-6-氟-1H-吲哚 50mg溶解於DMF　0.78mL中。於室溫添加碳酸銫　151mg、2,2-二甲基環氧乙烷 42μL，於90℃攪拌16小時。以飽和氯化銨水溶液進行驟冷，添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後，蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇。Example 289 "5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-3-fluoro-2' -(6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer- Synthesis of X 2 Hydrochloride (Step 1) 50 mg of 5-bromo-6-fluoro-1H-indole was dissolved in 0.78 mL of DMF. 151 mg of cesium carbonate and 42 µL of 2,2-dimethyloxirane were added at room temperature, and the mixture was stirred at 90°C for 16 hours. It was quenched with saturated ammonium chloride aqueous solution, ethyl acetate was added, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propane- 2-alcohol.

(步驟2)以實施例285(步驟8~11)為準，藉由使用前述步驟1所得到的1-(5-溴-6-氟-吲哚-1-基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-吲哚-苯并三唑-1-基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 285 (Steps 8-11), by using the 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl- Propan-2-ol was substituted for 1-(5-bromo-6,7-difluoro-indole-benzotriazol-1-yl)-2-methyl-propan-2-ol to obtain the title compound.

實施例290　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'',3-二氟-4''-(2-羥基-2-甲基丙基)-[1,1':2',1''-聯三苯]-4-甲腈-異構物-X 2鹽酸鹽之合成(步驟1)將甲基 2-(4-溴-3-氟-苯基)乙酸酯 500mg溶解於THF 2.2mL中。於-30℃滴下添加3M MeMgBr 二乙醚溶液 5.40mL，於室溫徹夜攪拌。將反應液注入氯化銨水溶液中，添加乙酸乙酯，並以水、飽和食鹽水依序洗淨。以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇。Example 290 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'',3- Difluoro-4''-(2-hydroxy-2-methylpropyl)-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-X 2 salt Synthesis of acid salt (Step 1) 500 mg of methyl 2-(4-bromo-3-fluoro-phenyl) acetate was dissolved in 2.2 mL of THF. 5.40 mL of 3M MeMgBr diethyl ether solution was added dropwise at -30°C, and stirred overnight at room temperature. The reaction solution was poured into an aqueous ammonium chloride solution, ethyl acetate was added, and washed with water and saturated brine in this order. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol.

(步驟2)以實施例285(步驟8~11)為準，藉由使用前述步驟1所得到的1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇，而得到標題化合物。(Step 2) Based on Example 285 (Steps 8 to 11), by using the 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propane-2- Alcohol replaces 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol to obtain the title compound.

實施例291　(S)-5'-((3-胺基吡咯啶-1-基)甲基)-2'',3-二氟-4''-(2-羥基-2-甲基丙基)-[1,1':2',1''-聯三苯]-4-甲腈 2鹽酸鹽之合成以實施例285(步驟8~11)為準，藉由使用實施例290(步驟1)獲得之1-(4-溴-3-氟-苯基)-2-甲基-丙烷-2-醇來代替1-(5-溴-6,7-二氟-苯并三唑-1-基)-2-甲基-丙烷-2-醇，並使用第三丁基　N-[(3S)-吡咯啶-3-基]胺甲酸酯來代替第三丁基　((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X，獲得標題化合物。Example 291 ``(S)-5'-((3-Aminopyrrolidin-1-yl)methyl)-2'',3-difluoro-4''-(2-hydroxy-2-methylpropane Base)-[1,1':2',1”-terphenyl]-4-carbonitrile 2 hydrochloride was synthesized in accordance with Example 285 (Steps 8-11), by using Example 290 (Step 1) The obtained 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol is substituted for 1-(5-bromo-6,7-difluoro-benzotri Azol-1-yl)-2-methyl-propan-2-ol, and use tertiary butyl N-[(3S)-pyrrolidin-3-yl]carbamate instead of tertiary butyl (( 1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X to obtain the title compound.

實施例292　5'-(1-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)乙基)-2'',3-二氟-4''-甲基-[1,1':2',1''-聯三苯]-4-甲腈-異構物-X 2鹽酸鹽之合成(步驟1)使1-(3-溴-4-氯-苯基)乙酮 2.00g溶解於1,4-二噁烷 14.3mL中。於室溫添加(4-氰基-3-氟-苯基)硼酸 1.55 g、PdCl2 (dppf)CH2 Cl2 188mg、2M碳酸鈉水溶液　10.7mL，並於90℃徹夜攪拌。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。添加二乙醚，濾取析出物，藉此獲得4-(5-乙醯基-2-氯-苯基)-2-苯甲腈。Example 292 5'-(1-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)ethyl)-2'', Synthesis of 3-difluoro-4''-methyl-[1,1':2',1''-terphenyl]-4-carbonitrile-isomer-X 2 hydrochloride (step 1) 2.00 g of 1-(3-bromo-4-chloro-phenyl)ethanone was dissolved in 14.3 mL of 1,4-dioxane. 1.55 g of (4-cyano-3-fluoro-phenyl)boronic acid, 188 mg of PdCl 2 (dppf)CH 2 Cl 2 and 10.7 mL of 2M sodium carbonate aqueous solution were added at room temperature, and the mixture was stirred at 90°C overnight. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. Diethyl ether was added, and the precipitate was collected by filtration to obtain 4-(5-acetoxy-2-chloro-phenyl)-2-benzonitrile.

(步驟2)將以前述步驟1獲得之4-(5-乙醯基-2-氯-苯基)-2-氟-苯甲腈 200mg、以實施例202(步驟2)合成之第三丁基 ((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X 160mg懸浮於1.0mL之正鈦酸四異丙酯中，並攪拌3天。添加EtOH 5mL、硼氫化鈉 138mg，攪拌1小時。以THF稀釋、添加矽藻土，並以矽藻土床過濾後，蒸餾去除溶劑。以矽膠管柱層析法(NH二氧化矽，移動相：己烷/乙酸乙酯)純化殘渣，藉此得到第三丁基 N-[(1S,3R,4R)-7-[1-[4-氯-3-(4-氰基-3-氟-苯基)苯基]乙基]-7-氮雜雙環[2.2.1]庚烷-3-基]胺甲酸酯。(Step 2) 200 mg of 4-(5-Acetyl-2-chloro-phenyl)-2-fluoro-benzonitrile obtained in the aforementioned step 1, and the tertiary butyl compound synthesized in Example 202 (Step 2) ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate-isomer-X 160mg suspended in 1.0mL of tetraisopropyl titanate Propyl ester and stir for 3 days. 5 mL of EtOH and 138 mg of sodium borohydride were added, and the mixture was stirred for 1 hour. After diluting with THF, adding diatomaceous earth, and filtering with a bed of diatomaceous earth, the solvent is distilled off. The residue was purified by silica gel column chromatography (NH silica, mobile phase: hexane/ethyl acetate) to obtain tertiary butyl N-[(1S,3R,4R)-7-[1-[ 4-Chloro-3-(4-cyano-3-fluoro-phenyl)phenyl]ethyl]-7-azabicyclo[2.2.1]heptan-3-yl]carbamate.

(步驟3)使以前述步驟2獲得之第三丁基 N-[(1S,3R,4R)-7-[1-[4-氯-3-(4-氰基-3-氟-苯基)苯基]乙基]-7-氮雜雙環[2.2.1]庚烷-3-基]胺甲酸酯 20mg溶解於DMF 0.50mL中。於室溫添加(2-氟-4-甲基-苯基)硼酸 19.7mg、S-Phos 1.75mg、Pd(dba)2 1.22mg、磷酸三鉀　27.1mg，於微波反應裝置中在160℃攪拌45分鐘。添加MTBE，並以水洗淨3次。接著以飽和食鹽水洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以逆相HPLC(移動相：水/乙腈)純化殘渣，並與目的之分餾一起以碳酸氫鈉水溶液中和，以氯仿萃取2次。蒸餾去除溶劑，使殘渣溶解於MeOH 1.0mL中，添加4當量濃度鹽酸-1,4-二噁烷溶液　1.0mL，攪拌30分鐘。將反應液之溶劑蒸餾去除，藉此得到標題化合物。(Step 3) Make the tertiary butyl N-[(1S,3R,4R)-7-[1-[4-chloro-3-(4-cyano-3-fluoro-phenyl ) Phenyl]ethyl]-7-azabicyclo[2.2.1]heptan-3-yl]carbamate 20 mg was dissolved in 0.50 mL of DMF. Add 19.7 mg of (2-fluoro-4-methyl-phenyl)boronic acid, 1.75 mg of S-Phos, 1.22 mg of Pd(dba) 2 and 27.1 mg of tripotassium phosphate at room temperature, and stir in a microwave reactor at 160°C 45 minutes. Add MTBE and wash with water 3 times. Then it was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile), neutralized with an aqueous sodium bicarbonate solution together with the desired fractionation, and extracted twice with chloroform. The solvent was distilled off, the residue was dissolved in 1.0 mL of MeOH, 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred for 30 minutes. The solvent of the reaction liquid was distilled off to obtain the title compound.

實施例293　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(1-(2-乙基-2-羥基丁基)-6，7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成以實施例285(步驟4~11)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 293 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(1- (2-Ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1 The synthesis of'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride is based on Example 285 (steps 4 to 11), by using 3-(aminomethyl)pentane-3 -Alcohol instead of 1-amino-2-methyl-propan-2-ol to obtain the title compound.

實施例294　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1，1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成(步驟1)將2-溴-1,3-二氟-4-硝基-苯 3.00 g溶解於THF 31.5mL中。添加TEA 2.63mL、1-胺基-2-甲基-丙烷-2-醇 1.40mL，於室溫攪拌1小時。添加乙酸乙酯，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(2-溴-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。Example 294 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(7- Bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1, Synthesis of 1'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride (Step 1) Dissolve 3.00 g of 2-bromo-1,3-difluoro-4-nitro-benzene in THF 31.5mL. Add 2.63 mL of TEA and 1.40 mL of 1-amino-2-methyl-propan-2-ol, and stir at room temperature for 1 hour. Add ethyl acetate, wash with water and saturated brine in this order, dry the organic layer with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propane -2-ol.

(步驟2)將前述步驟1所得到的1-(2-溴-3-氟-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.03g溶解於乙酸 6.7mL中。於室溫添加N-碘琥珀醯亞胺 981mg，於50℃攪拌3小時。添加MTBE、水，並以MTBE萃取2次。以無水硫酸鈉乾燥合起來的有機層後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(2-溴-3-氟-4-碘-6-硝基-苯胺基)-2-甲基-丙烷-2-醇。(Step 2) Dissolve 1.03 g of 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 1 above in 6.7 mL of acetic acid. 981 mg of N-iodosuccinimide was added at room temperature, and the mixture was stirred at 50°C for 3 hours. Add MTBE, water, and extract twice with MTBE. After drying the combined organic layer with anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-bromo-3-fluoro-4-iodo-6-nitro-anilino)-2- Methyl-propan-2-ol.

(步驟3)將前述步驟2所得到的1-(2-溴-3-氟-4-碘-6-硝基-苯胺基)-2-甲基-丙烷-2-醇 1.33g及鐵粉1.33g懸浮於THF 10.2mL、2當量濃度鹽酸 10.2mL中，於60℃攪拌1小時。添加MTBE，進行矽藻土過濾。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(6-胺基-2-溴-3-氟-4-碘-苯胺基)-2-甲基-丙烷-2-醇。(Step 3) Combine 1.33 g of 1-(2-bromo-3-fluoro-4-iodo-6-nitro-anilino)-2-methyl-propan-2-ol obtained in step 2 above and iron powder 1.33g was suspended in 10.2mL of THF and 10.2mL of 2N hydrochloric acid, and stirred at 60°C for 1 hour. Add MTBE and filter with diatomaceous earth. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2- Methyl-propan-2-ol.

(步驟4)將前述步驟3所得到的1-(6-胺基-2-溴-3-氟-4-碘-苯胺基)-2-甲基-丙烷-2-醇 940mg溶解於水1.88mL、THF 4.7mL中。於0℃添加12當量濃度鹽酸2.82mL、亞硝酸鈉水溶液(使亞硝酸鈉209mg溶解於水0.63mL而成者)，於室溫攪拌1小時。添加MTBE，以水、飽和食鹽水依序洗淨，以無水硫酸鈉乾燥後蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到1-(7-溴-6-氟-5-碘-苯并三唑-1-基)-2-甲基-丙烷-2-醇。(Step 4) Dissolve 940 mg of 1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2-methyl-propan-2-ol obtained in step 3 above in water 1.88 mL, THF 4.7mL. At 0°C, 2.82 mL of 12-N hydrochloric acid and an aqueous sodium nitrite solution (dissolved 209 mg of sodium nitrite in 0.63 mL of water) were added, and the mixture was stirred at room temperature for 1 hour. Add MTBE, wash with water and saturated brine in order, dry with anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(7-bromo-6-fluoro-5-iodo-benzotriazol-1-yl)-2 -Methyl-propan-2-ol.

(步驟5)將實施例285(步驟3)所得到的第三丁基 3-(4-氰基-3-氟-苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲酸酯 3g、及前述步驟5所得到的1-(7-溴-6-氟-5-碘-苯并三唑-1-基)-2-甲基-丙烷-2-醇 3.228g溶解於1,4-二噁烷23.6mL中。於室溫添加PdCl2 (PPh3 )2 398mg、磷酸三鉀　4.513 g，並氮取代、脫氣，於100℃撤夜攪拌。將反應液進行矽藻土過濾，並蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。對殘渣添加THF 45.0mL、12當量濃度鹽酸 45.0mL，並於室溫攪拌2小時。添加MTBE、水並分液，在將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，蒸餾去除溶劑。將殘渣自二乙醚/己烷結晶化，藉此獲得4-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-3-(4-氰基-3-氟-苯基)苯甲酸。(Step 5) The tertiary butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate 3g, and the 1-(7-bromo-6-fluoro-5-iodo-benzotriazole obtained in step 5 above) 3.228 g of -1-yl)-2-methyl-propan-2-ol was dissolved in 23.6 mL of 1,4-dioxane. Add 398 mg of PdCl 2 (PPh 3 ) 2 and 4.513 g of tripotassium phosphate at room temperature, replace with nitrogen, degas, and stir overnight at 100°C. The reaction solution was filtered through Celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was distilled off. To the residue, 45.0 mL of THF and 45.0 mL of 12-N hydrochloric acid were added, and the mixture was stirred at room temperature for 2 hours. MTBE and water were added for liquid separation, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was crystallized from diethyl ether/hexane to obtain 4-[7-bromo-6-fluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]- 3-(4-cyano-3-fluoro-phenyl)benzoic acid.

(步驟6)使以前述步驟5獲得之4-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-3-(4-氰基-3-氟-苯基)苯甲酸 88.0mg溶解於THF 0.834mL中。於室溫添加WSC・HCl 64.0mg、HOBt 51.1mg，並在室溫下攪拌20分鐘。添加硼氫化鈉 18.9mg，攪拌1小時。將反應液於減壓下蒸餾去除溶劑。以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-[2-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-(羥甲基)苯基]-2-氟-苯甲腈。(Step 6) Make 4-(7-bromo-6-fluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl)-3-( 88.0 mg of 4-cyano-3-fluoro-phenyl)benzoic acid was dissolved in 0.834 mL of THF. 64.0 mg of WSC·HCl and 51.1 mg of HOBt were added at room temperature, and the mixture was stirred at room temperature for 20 minutes. 18.9 mg of sodium borohydride was added, and the mixture was stirred for 1 hour. The reaction liquid was distilled off under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-[2-[7-bromo-6-fluoro-1-(2-hydroxy-2-methyl- Propyl)benzotriazol-5-yl]-5-(hydroxymethyl)phenyl]-2-fluoro-benzonitrile.

(步驟7)將以前述步驟6獲得之4-[2-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-(羥甲基)苯基]-2-氟-苯甲腈 43.5mg溶解於DCM 0.847mL中。於室溫添加DESS-MARTIN過碘烷 39.5mg，並於室溫撤夜攪拌。減壓濃縮反應液，以矽膠管柱層析法(移動相：己烷/乙酸乙酯)純化殘渣，藉此得到4-[2-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-甲醯基-苯基]-2-氟-苯甲腈。(Step 7) The 4-[2-[7-bromo-6-fluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]- 43.5 mg of 5-(hydroxymethyl)phenyl]-2-fluoro-benzonitrile was dissolved in 0.847 mL of DCM. 39.5 mg of DESS-MARTIN periodinane was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-[2-[7-bromo-6-fluoro-1-(2-hydroxyl) -2-Methyl-propyl)benzotriazol-5-yl]-5-methanyl-phenyl]-2-fluoro-benzonitrile.

(步驟8)將以前述步驟7獲得之4-[2-[7-溴-6-氟-1-(2-羥基-2-甲基-丙基)苯并三唑-5-基]-5-甲醯基-苯基]-2-氟-苯甲腈 37.2mg溶解於DCM 1.00mL中。於室溫添加以實施例202(步驟2)合成之第三丁基 ((1S,2S,4R)-rel-7-氮雜雙環[2.2.1]庚烷-2-基)胺甲酸酯-異構物-X　30.9mg，並於室溫攪拌30分鐘。於室溫添加三乙醯氧基硼氫化鈉 27.8mg，並於室溫下撤夜攪拌。添加氯仿，濾別不溶物，並蒸餾去除溶劑。以矽膠管柱層析法(NH矽膠，移動相：己烷/乙酸乙酯)純化殘渣，並蒸餾去除溶劑。將殘渣溶解於MeOH 1.0mL中，添加4當量濃度鹽酸-1,4-二噁烷溶液 1.0mL，並攪拌30分鐘。將反應液之溶劑蒸餾去除，藉此得到標題化合物。(Step 8) The 4-[2-[7-bromo-6-fluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]- 37.2 mg of 5-methanyl-phenyl]-2-fluoro-benzonitrile was dissolved in 1.00 mL of DCM. Add the tertiary butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]heptan-2-yl)carbamate synthesized in Example 202 (Step 2) at room temperature -Isomer-X "30.9 mg, and stirred at room temperature for 30 minutes. 27.8 mg of sodium triacetoxyborohydride was added at room temperature, and the mixture was stirred overnight at room temperature. Add chloroform, filter out the insoluble matter, and distill to remove the solvent. The residue was purified by silica gel column chromatography (NH silica gel, mobile phase: hexane/ethyl acetate), and the solvent was distilled off. The residue was dissolved in 1.0 mL of MeOH, 1.0 mL of a 4-eq hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred for 30 minutes. The solvent of the reaction liquid was distilled off to obtain the title compound.

實施例295　5'-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2'-(7-溴-1-(2-乙基-2-羥基丁基)-6-氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1，1'-聯苯]-4-甲腈-異構物-X 2鹽酸鹽之合成以實施例294(步驟1~8)為準，藉由使用3-(胺基甲基)戊烷-3-醇來代替1-胺基-2-甲基-丙烷-2-醇，而得到標題化合物。Example 295 ``5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)methyl)-2'-(7- Bromo-1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1, The synthesis of 1'-biphenyl]-4-carbonitrile-isomer-X 2 hydrochloride is based on Example 294 (steps 1 to 8), by using 3-(aminomethyl)pentane- The 3-alcohol was substituted for 1-amino-2-methyl-propan-2-ol to obtain the title compound.

以下顯示實施例1~295之化合物一覧。The following shows a summary of the compounds of Examples 1 to 295.

[化學式55]

Figure 02_image001
[Chemical formula 55]
Figure 02_image001

在下述表中，當In the following table, when

[化學式56]

Figure 02_image085
[Chemical formula 56]
Figure 02_image085

之結構被記載成The structure is recorded as

[化學式57]

Figure 02_image087
[Chemical formula 57]
Figure 02_image087

時，表示具有, Means having

[化學式58]

Figure 02_image089
[Chemical formula 58]
Figure 02_image089

結構之化合物的混合物，當記載為A mixture of compounds of the structure, when recorded as

[化學式59]

Figure 02_image091
[Chemical formula 59]
Figure 02_image091

時，表示具有, Means having

[化學式60]

Figure 02_image093
[Chemical formula 60]
Figure 02_image093

結構之化合物的混合物，當記載為A mixture of compounds of the structure, when recorded as

[化學式61]

Figure 02_image095
[Chemical formula 61]
Figure 02_image095

時，表示具有, Means having

[化學式62]

Figure 02_image097
[Chemical formula 62]
Figure 02_image097

之任一結構的化合物。The compound of any structure.

「salf　form」表示鹽形態。「free」表示自由體。"Salf　form" means salt form. "Free" means free body.

[表1]

Figure 02_image099
[Table 1]
Figure 02_image099

[表2]

Figure 02_image101
[Table 2]
Figure 02_image101

[表3]

Figure 02_image103
[table 3]
Figure 02_image103

[表4]

Figure 02_image105
[Table 4]
Figure 02_image105

[表5]

Figure 02_image107
[table 5]
Figure 02_image107

[表6]

Figure 02_image109
[Table 6]
Figure 02_image109

[表7]

Figure 02_image111
[Table 7]
Figure 02_image111

[表8]

Figure 02_image113
[Table 8]
Figure 02_image113

[表9]

Figure 02_image115
[Table 9]
Figure 02_image115

[表10]

Figure 02_image117
[Table 10]
Figure 02_image117

[表11]

Figure 02_image119
[Table 11]
Figure 02_image119

[表12]

Figure 02_image121
[Table 12]
Figure 02_image121

[表13]

Figure 02_image123
[Table 13]
Figure 02_image123

[表14]

Figure 02_image125
[Table 14]
Figure 02_image125

[表15]

Figure 02_image127
[Table 15]
Figure 02_image127

[表16]

Figure 02_image129
[Table 16]
Figure 02_image129

[表17]

Figure 02_image131
[Table 17]
Figure 02_image131

[表18]

Figure 02_image133
[Table 18]
Figure 02_image133

[表19]

Figure 02_image135
[Table 19]
Figure 02_image135

[表20]

Figure 02_image137
[Table 20]
Figure 02_image137

[表21]

Figure 02_image139
[Table 21]
Figure 02_image139

[表22]

Figure 02_image141
[Table 22]
Figure 02_image141

[表23]

Figure 02_image143
[Table 23]
Figure 02_image143

[表24]

Figure 02_image145
[Table 24]
Figure 02_image145

[表25]

Figure 02_image147
[Table 25]
Figure 02_image147

[表26]

Figure 02_image149
[Table 26]
Figure 02_image149

[表27]

Figure 02_image151
[Table 27]
Figure 02_image151

[表28]

Figure 02_image153
[Table 28]
Figure 02_image153

[表29]

Figure 02_image155
[Table 29]
Figure 02_image155

[表30]

Figure 02_image157
[Table 30]
Figure 02_image157

[表31]

Figure 02_image159
[Table 31]
Figure 02_image159

[表32]

Figure 02_image161
[Table 32]
Figure 02_image161

[表33]

Figure 02_image163
[Table 33]
Figure 02_image163

[表34]

Figure 02_image165
[Table 34]
Figure 02_image165

[表35]

Figure 02_image167
[Table 35]
Figure 02_image167

[表36]

Figure 02_image169
[Table 36]
Figure 02_image169

[表37]

Figure 02_image171
[Table 37]
Figure 02_image171

試驗例1　LSD1抑制活性(活體外(in vitro))之測量關於對LSD1活性之化合物的抑制活性測量之條件，係將可從PerkinElmer公司之網頁獲得的資料(U-TRF ＃38)及Glaxosmithkline公司之專利(WO2012135113)作為參考來設定。Test Example 1 "Measurement of LSD1 Inhibitory Activity (in vitro) The conditions for measuring the inhibitory activity of compounds against LSD1 activity are based on the information (U-TRF #38) available from PerkinElmer's website (U-TRF #38) and Glaxosmithkline The patent (WO2012135113) is set as a reference.

在化合物之抑制活性測量中，首先以二甲基亞碸(DMSO)分階段稀釋實施例化合物。接著，在反應用緩衝液(25mM Tris-HCl(pH7.5)、50mM KCl、2mM CHAPS、1mM DTT、0.02% BSA)中添加經分階段稀釋的實施例化合物DMSO溶液(DMSO之最終濃度為5%)及人類LSD1蛋白質(Abcam公司 ab80379)，於25℃預培養30分鐘。其後，添加H3K4(Me1)-biotin labeled peptide(Anaspec公司 ＃64355)(最終濃度為200nM)，使其反應60分鐘。對其添加Tranylcypromine(最終濃度為3mM)而使反應停止後，添加包含Eu標定化抗H3K4抗體(PerkinElmer公司 TRF0404)及Streptavidin Alexa Fluor 647(Thermo Fisher Scientific公司 S21374)之檢測液，於室溫靜置1小時。最後，使用PHERAstar FS(BMG LABTECH公司)在620nm及665nm之二波長測量波長337nm之激發光照射時的螢光量。從二波長之螢光量比求出去甲基化反應量，而將可抑止50%去甲基化反應之化合物濃度定義成IC50値(nM)並示於以下表。In the measurement of the inhibitory activity of the compounds, the example compounds were first diluted with dimethyl sulfoxide (DMSO) in stages. Next, the DMSO solution of the example compound diluted in stages (the final concentration of DMSO is 5 mM) was added to the reaction buffer (25 mM Tris-HCl (pH 7.5), 50 mM KCl, 2 mM CHAPS, 1 mM DTT, 0.02% BSA). %) and human LSD1 protein (Abcam ab80379), pre-incubate at 25°C for 30 minutes. After that, H3K4(Me1)-biotin labeled peptide (Anaspec Corporation #64355) (final concentration of 200 nM) was added and allowed to react for 60 minutes. After adding Tranylcypromine (final concentration of 3mM) to stop the reaction, add a detection solution containing Eu-calibrated anti-H3K4 antibody (TRF0404 from PerkinElmer) and Streptavidin Alexa Fluor 647 (S21374 from Thermo Fisher Scientific), and let stand at room temperature 1 hour. Finally, PHERAstar FS (BMG LABTECH) was used to measure the amount of fluorescence when irradiated by excitation light with a wavelength of 337nm at 620nm and 665nm. The methylation reaction amount is calculated from the ratio of the fluorescence amount of the two wavelengths, and the concentration of the compound that can inhibit the demethylation reaction by 50% is defined as the IC50 value (nM) and shown in the following table.

[表38]

Figure 02_image173
[Table 38]
Figure 02_image173

[表39]

Figure 02_image175
[Table 39]
Figure 02_image175

從此試驗結果可明瞭，通式(I)表示的聯苯化合物具有LSD1抑制活性。From the test results, it is clear that the biphenyl compound represented by the general formula (I) has LSD1 inhibitory activity.

試驗例2　細胞增殖抑止試驗藉由以下條件實施針對HEL細胞(人類急性骨髄性白血病細胞株)、NCI-H1417細胞(人類小細胞肺癌細胞株)及NCI-H146細胞(人類小細胞肺癌細胞株)之活體外細胞增殖抑止試驗。Test Example 2 The cell proliferation inhibition test was performed against HEL cells (human acute bone leukemia cell line), NCI-H1417 cells (human small cell lung cancer cell line), and NCI-H146 cells (human small cell lung cancer cell line) under the following conditions In vitro cell proliferation inhibition test.

將經培養於包含10%FBS之RPMI1640培養基(Thermo Fisher Scientific、Cat＃：A10491-01)中而得之HEL細胞(JCRB、Cat＃：JCRB0062)、NCI-H1417細胞(ATCC、Cat＃：CRL-5869)或NCI-H146細胞(ATCC、Cat＃：HTB-173)，在96孔平底微量盤(Thermo Fisher Scientific、Cat＃：165305)中以每1孔之細胞數成為HEL細胞1500個(100μL)、NCI-H1417細胞5000個(100μL)、NCI-H146細胞1200個(100μL)的方式進行播種。以二甲基亞碸將實施例化合物分階段稀釋成最終濃度的500倍之濃度。將經分階段稀釋的實施例化合物或者僅將二甲基亞碸添加至包含10%FBS之RPMI1640培養基中，以使得成為最終濃度的2倍濃度。將其在先前所述的HEL細胞、NCI-H1417細胞或NCI-H146細胞之培養盤的各孔中各添加100μL，而使得實施例化合物之最終濃度分別成為3000、1000、300、100、30、10、3、1、0.3、0.1、0.03、0.01nM。令二甲基亞碸的最終濃度成為0.2%。添加有實施例化合物或僅添加二甲基亞碸之細胞係在37℃、含有5%二氧化碳之培養器中培養5日 (HEL細胞)或10日(NCI-H1417細胞及NCI-H146細胞)。培養後，於室溫放置30分鐘，從各孔各去除上清液100μL，而令其殘留100μL之細胞培養液。對殘留的細胞培養液100μL添加等量的CellTiter-Glo 2.0 Assay (Promega，Cat＃：G9242)。以盤混合器振盪1分鐘，其後在暗處放置10分鐘之後，以微量盤讀取器 (PerkinElmer，EnSpire)測量各孔來自活細胞的發光量。藉由以下式計算出細胞增殖率，求得細胞增殖率成為50%之濃度，亦即抑制50%細胞增殖之受測化合物的濃度(IC50値(nM))。HEL cells (JCRB, Cat#: JCRB0062), NCI-H1417 cells (ATCC, Cat#: CRL- 5869) or NCI-H146 cells (ATCC, Cat#: HTB-173), in a 96-well flat-bottom microplate (Thermo Fisher Scientific, Cat#: 165305), the number of cells per well becomes 1500 HEL cells (100μL) , 5000 NCI-H1417 cells (100μL) and 1200 NCI-H146 cells (100μL) for seeding. The compound of the examples was diluted stepwise with dimethyl sulfoxide to a concentration of 500 times the final concentration. The compound of the example diluted in stages or only dimethylsulfoxide was added to the RPMI1640 medium containing 10% FBS so as to be twice the final concentration. Add 100 μL to each well of the previously described HEL cell, NCI-H1417 cell or NCI-H146 cell culture plate, so that the final concentration of the compound of the example becomes 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01nM. Let the final concentration of dimethyl sulfide become 0.2%. The cell line added with the compound of the example or added only with dimethyl sulfoxide was cultured in an incubator containing 5% carbon dioxide at 37°C for 5 days (HEL cells) or 10 days (NCI-H1417 cells and NCI-H146 cells). After incubation, place it at room temperature for 30 minutes, and remove 100 μL of supernatant from each well, leaving 100 μL of cell culture solution remaining. Add the same amount of CellTiter-Glo 2.0 Assay (Promega, Cat#: G9242) to 100 μL of the remaining cell culture medium. After shaking with a disc mixer for 1 minute, and then leaving it in the dark for 10 minutes, the amount of luminescence from living cells in each well was measured with a microplate reader (PerkinElmer, EnSpire). The cell proliferation rate is calculated by the following formula, and the concentration at which the cell proliferation rate becomes 50%, that is, the concentration of the test compound that inhibits cell proliferation by 50% (IC50 value (nM)) is obtained.

細胞增殖率(%)＝T/C×100T：添加有受測化合物之孔的發光量(每秒計數)C：僅添加有二甲基亞碸之孔的發光量(每秒計數)。Cell proliferation rate (%)=T/C×100T: the amount of luminescence of the wells added with the test compound (counts per second) C: the amount of luminescence of the wells only added with dimethylsulfide (counts per second).

將結果示於下表。The results are shown in the table below.

[表40]

Figure 02_image177
[Table 40]
Figure 02_image177

[表41]

Figure 02_image179
[Table 41]
Figure 02_image179

[表42]

Figure 02_image181
[Table 42]
Figure 02_image181

[表43]

Figure 02_image183
[Table 43]
Figure 02_image183

[表44]

Figure 02_image185
[Table 44]
Figure 02_image185

此試驗的結果可清楚瞭解到通式(I)表示的聯苯化合物顯示活體外的細胞增殖抑制效果，不僅會顯示重組人類LSD1蛋白質之活性抑制，亦顯示對癌細胞增殖之抑止效果，而暗示其作為抗腫瘤劑係有用的。The results of this test can clearly understand that the biphenyl compound represented by the general formula (I) exhibits an in vitro cell proliferation inhibitory effect. It not only shows the activity inhibition of the recombinant human LSD1 protein, but also shows an inhibitory effect on the proliferation of cancer cells. It is useful as an antitumor agent.

試驗例3　使用NCI-H146細胞(人類小細胞肺癌細胞株)之抗腫瘤效果試驗於BALB/cAJcl-nu/nu小鼠之皮下移植3.5×106 cells(100μL)的NCI-H146細胞，並將腫瘤體積在100-300mm3 之範圍內的個體，以平均腫瘤體積均一的方式進行分群。對各群5隻小鼠口服投予載劑(vehicle)(0.1N HCL含有0.5%羥基甲基丙基纖維素)或是實施例化合物。投予係每日連續且在21日之間(實施例化合物41)，或28日之間(實施例化合物37、161、166、175、176及177)1日進行1次。每週2次使用電子游標尺分別測量腫瘤的長徑及短徑而計算腫瘤體積(tumor volume，TV)。從計算出的腫瘤體積計算相對腫瘤體積(relative tumor volume，RTV)及相對腫瘤體積變化率(T/C(%))。TV、RTV及T/C(%)係藉由次式計算出。Test Example 3 The anti-tumor effect test using NCI-H146 cells (human small cell lung cancer cell line) was subcutaneously transplanted with 3.5×10 6 cells (100 μL) of NCI-H146 cells in BALB/cAJcl-nu/nu mice, and Individuals whose tumor volume is within the range of 100-300 mm 3 are classified into groups with a uniform average tumor volume. A vehicle (0.1N HCL containing 0.5% hydroxymethylpropylcellulose) or the compound of the example was orally administered to 5 mice in each group. The administration was carried out continuously and once a day between 21 days (Example Compound 41) or 28 days (Example Compounds 37, 161, 166, 175, 176, and 177). Twice a week, an electronic vernier was used to measure the long and short diameters of the tumor to calculate the tumor volume (TV). Calculate the relative tumor volume (RTV) and relative tumor volume change rate (T/C(%)) from the calculated tumor volume. TV, RTV and T/C (%) are calculated by the following formula.

腫瘤體積TV(mm3 )＝(長徑,mm)×(短徑,mm)×(短徑,mm)/2相對腫瘤體積RTV＝TV/(分群日之TV)T/C(%)＝(投予群之平均RTV)/(載劑投予群之平均RTV)×100。Tumor volume TV (mm 3 )=(long diameter, mm)×(short diameter, mm)×(short diameter, mm)/2 Relative tumor volume RTV=TV/(TV of grouping day) T/C(%)= (Average RTV of the administration group)/(Average RTV of the vehicle administration group)×100.

將結果示於下表。The results are shown in the table below.

[表45]

Figure 02_image187
[Table 45]
Figure 02_image187

最終測量日係設為最終投予日的隔日，通式(I)表示的聯苯化合物於前述藥效評定模式顯示抗腫瘤效果，又，最終測量日的體重減少率係小於投予前(day0)之體重的20%。The final measurement day was set as the next day after the final administration day. The biphenyl compound represented by the general formula (I) showed an anti-tumor effect in the aforementioned pharmacodynamic evaluation mode. Moreover, the weight loss rate on the final measurement day was less than that before the administration (day0 ) 20% of the body weight.

可知通式(I)表示的聯苯化合物或其鹽具有優異的LSD1抑制活性，且顯示對癌細胞株的增殖抑止效果，並且毒性低，可進行口服投予。因此，通式(I)表示的聯苯化合物或其鹽作為癌之預防及/或治療劑係十分有用的。It can be seen that the biphenyl compound represented by the general formula (I) or a salt thereof has excellent LSD1 inhibitory activity, exhibits a proliferation inhibitory effect on cancer cell lines, has low toxicity, and can be administered orally. Therefore, the biphenyl compound represented by the general formula (I) or its salt is very useful as a preventive and/or therapeutic agent for cancer.

試驗例4　使用有人類AML細胞株或人類骨髄增生異常症候群(MDS)細胞株之聯苯化合物與其他抗腫瘤劑的組合(in vitro)各試劑之獲取來源、腫瘤細胞株之獲取來源、使用培養基、細胞播種數顯示於下表。Test Example 4 　 Combinations of biphenyl compounds with human AML cell lines or human bone malignant syndrome (MDS) cell lines and other anti-tumor agents (in vitro) Source of each reagent, source of tumor cell line, and use of culture medium The number of cell seeding is shown in the table below.

[表46]

Figure 107117996-A0304-0001
[Table 46]
Figure 107117996-A0304-0001

[表47]

Figure 107117996-A0304-0002
[Table 47]
Figure 107117996-A0304-0002

細胞是以20μL/孔來播種到384孔培養盤(corning)。將播種好細胞之盤在已設定為37℃、5%　CO2 的培養器内培養。播種當日，將已混合各種濃度組合之聯苯化合物與其他具有抗腫瘤效果之化合物的藥液添加至細胞。詳細來說，使用含有20% FBS之RPMI-1640培養基(ATCC組成培養基)，或含有10% FBS及10ng/mL　IL-3、50μM 2-ME之RPMI-1640培養基，針對聯苯化合物(實施例化合物37、41、166、177、214、273、285)是調製10階段的系列稀釋液(包含0nM)、針對其他具有抗腫瘤效果之化合物是調製8階段的系列稀釋(包含0nM)。將已等量分注各化合物系列稀釋液的藥液以1比1之比來混合，調製出全部組合計共80種的混合藥液。下表顯示各藥劑之最高濃度(以最終濃度表示)及公比。將該混合藥液以5μL/孔(N＝4)添加到盤中後，進一步以37℃、5% CO2 的條件培養10天。10天後，將CellTiter-Glo 2.0　Assay(Promega、Cat＃：G9242)以25μL/孔來添加，並將化學發光以盤讀取儀(EnSpire(註冊商標)Multimode Plate Reader，PerkinElmer Japan Co., Ltd)測定。The cells are seeded into a 384-well corning dish at 20 μL/well. The seeded cells were cultured in an incubator set at 37°C and 5% CO 2. On the day of planting, add a medicinal solution containing various combinations of biphenyl compounds and other compounds with anti-tumor effects to the cells. In detail, use RPMI-1640 medium containing 20% FBS (ATCC composition medium), or RPMI-1640 medium containing 10% FBS, 10ng/mL IL-3, 50μM 2-ME, for biphenyl compounds (Example Compounds 37, 41, 166, 177, 214, 273, 285) are prepared 10-stage serial dilutions (including 0 nM), and for other compounds with anti-tumor effects, 8-stage serial dilutions (including 0 nM) are prepared. The medicinal solutions in which the serial dilutions of each compound have been dispensed in equal amounts are mixed at a ratio of 1:1 to prepare a total of 80 mixed medicinal solutions for all combinations. The following table shows the highest concentration (expressed as the final concentration) and common ratio of each agent. After adding 5 μL/well (N=4) of the mixed drug solution to the dish, it was further cultured under the conditions of 37°C and 5% CO 2 for 10 days. After 10 days, CellTiter-Glo 2.0 Assay (Promega, Cat#: G9242) was added at 25 μL/well, and chemiluminescence was used in a disk reader (EnSpire (registered trademark) Multimode Plate Reader, PerkinElmer Japan Co., Ltd. ) Determination.

[表48]

Figure 107117996-A0304-0003
[Table 48]
Figure 107117996-A0304-0003

針對藥劑之併用所產生之效果增強，是依記載於習知文獻(Trends　Pharmacol.Sci., 4, 450-454, 1983, Pharmacol　Rev., 58(3), 621-81, 2006)之方法為準來評價。具體而言，針對以各個單劑接受聯苯化合物及其他具有抗腫瘤效果之化合物之處理的細胞，透過與對照細胞進行比較，求出經標準之細胞生存率；T/C(Treatment/Control比、%)。從獲得之T/C值，透過使用有回歸分析工具XLfit5.3(IDBS Ltd.)之曲線擬合(Curve fitting)的回歸分析工具決定對各藥劑之半數抑制濃度(IC50)。將各個單劑之IC50比以下式算出。IC50比＝[聯苯化合物之IC50]：[其他具有抗腫瘤效果之化合物的IC50]。The enhancement of the effect produced by the combined use of drugs is based on the method described in the conventional literature (Trends　Pharmacol.Sci., 4, 450-454, 1983, Pharmacol　Rev., 58(3), 621-81, 2006): Standard to evaluate. Specifically, for cells treated with a single dose of biphenyl compounds and other compounds with anti-tumor effects, the standard cell survival rate was calculated by comparing with control cells; T/C (Treatment/Control ratio) , %). From the obtained T/C value, the half inhibitory concentration (IC50) of each agent was determined by using the regression analysis tool XLfit5.3 (IDBS Ltd.)'s curve fitting (Curve fitting) regression analysis tool. The IC50 ratio of each single agent is calculated by the following formula. IC50 ratio = [IC50 of biphenyl compound]: [IC50 of other compounds with antitumor effect].

針對實際上實驗所使用2化合物之濃度比的組合，使用各自的T/C，求出併用兩化合物時之半數抑制濃度(ED50)。針對各個組合，求出該等ED50中的合併指數(combination index, CI)、抑制率(Fraction affected, Fa)。CI之算出是使用計算Median Effect法之中位效應分析軟體CalcuSyn 2.0(CalcuSyn, Inc.)。For the combination of the concentration ratios of the two compounds used in the actual experiment, the respective T/C was used to determine the half inhibitory concentration (ED50) when the two compounds were used in combination. For each combination, the combination index (CI) and the inhibition rate (Fraction affected, Fa) in the ED50 were obtained. The calculation of CI is calculated by the calculation of the Median Effect method, the median effect analysis software CalcuSyn 2.0 (CalcuSyn, Inc.).

併用效果是如下表來判定(Pharmacol　Rev., 58(3), p.621-81, 2006)。The effect of the combined use is determined by the following table (Pharmacol　 Rev., 58(3), p.621-81, 2006).

[表49]

Figure 107117996-A0304-0004
[Table 49]
Figure 107117996-A0304-0004

將結果示於下表。The results are shown in the table below.

[表50]

Figure 107117996-A0304-0005
[Table 50]
Figure 107117996-A0304-0005

[表51]

Figure 107117996-A0304-0006
[Table 51]
Figure 107117996-A0304-0006

[表52]

Figure 107117996-A0304-0007
[Table 52]
Figure 107117996-A0304-0007

[表53]

Figure 107117996-A0304-0008
[Table 53]
Figure 107117996-A0304-0008

[表54]

Figure 107117996-A0304-0009
[Table 54]
Figure 107117996-A0304-0009

[表55]

Figure 107117996-A0304-0010
[Table 55]
Figure 107117996-A0304-0010

[表56]

Figure 107117996-A0304-0011
[Table 56]
Figure 107117996-A0304-0011

[表57]

Figure 107117996-A0304-0012
[Table 57]
Figure 107117996-A0304-0012

[表58]

Figure 107117996-A0304-0013
[Table 58]
Figure 107117996-A0304-0013

[表59]

Figure 107117996-A0304-0014
[Table 59]
Figure 107117996-A0304-0014

[表60]

Figure 107117996-A0304-0015
[Table 60]
Figure 107117996-A0304-0015

[表61]

Figure 107117996-A0304-0016
[Table 61]
Figure 107117996-A0304-0016

[表62]

Figure 107117996-A0304-0017
[Table 62]
Figure 107117996-A0304-0017

[表63]

Figure 107117996-A0304-0018
[Table 63]
Figure 107117996-A0304-0018

[表64]

Figure 107117996-A0304-0019
[Table 64]
Figure 107117996-A0304-0019

[表65]

Figure 107117996-A0304-0020
[Table 65]
Figure 107117996-A0304-0020

[表66]

Figure 107117996-A0304-0021
[Table 66]
Figure 107117996-A0304-0021

[表67]

Figure 107117996-A0304-0022
[Table 67]
Figure 107117996-A0304-0022

[表68]

Figure 107117996-A0304-0023
[Table 68]
Figure 107117996-A0304-0023

[表69]

Figure 107117996-A0304-0024
[Table 69]
Figure 107117996-A0304-0024

[表70]

Figure 107117996-A0304-0025
[Table 70]
Figure 107117996-A0304-0025

[表71]

Figure 107117996-A0304-0026
[Table 71]
Figure 107117996-A0304-0026

[表72]

Figure 107117996-A0304-0027
[Table 72]
Figure 107117996-A0304-0027

[表73]

Figure 107117996-A0304-0028
[Table 73]
Figure 107117996-A0304-0028

[表74]

Figure 107117996-A0304-0029
[Table 74]
Figure 107117996-A0304-0029

[表75]

Figure 107117996-A0304-0030
[Table 75]
Figure 107117996-A0304-0030

[表76]

Figure 107117996-A0304-0031
[Table 76]
Figure 107117996-A0304-0031

[表77]

Figure 107117996-A0304-0032
[Table 77]
Figure 107117996-A0304-0032

[表78]

Figure 107117996-A0304-0033
[Table 78]
Figure 107117996-A0304-0033

[表79]

Figure 107117996-A0304-0034
[Table 79]
Figure 107117996-A0304-0034

[表80]

Figure 107117996-A0304-0035
[Table 80]
Figure 107117996-A0304-0035

[表81]

Figure 107117996-A0304-0036
[Table 81]
Figure 107117996-A0304-0036

[表82]

Figure 107117996-A0304-0037
[Table 82]
Figure 107117996-A0304-0037

[表83]

Figure 107117996-A0304-0038
[Table 83]
Figure 107117996-A0304-0038

[表84]

Figure 107117996-A0304-0039
[Table 84]
Figure 107117996-A0304-0039

該結果顯示，聯苯化合物透過與代謝拮抗劑之阿糖胞苷、地西他濱、氮雜胞苷、全反式維甲酸之維A酸(ATRA)、或抗腫瘤抗生素之道諾黴素併用，抗腫瘤效果會協同的增強。The results showed that the biphenyl compound penetrates with the metabolic antagonist cytarabine, decitabine, azacytidine, all-trans retinoic acid (ATRA), or the antitumor antibiotic daunorubicin When used together, the anti-tumor effect will be synergistically enhanced.

試驗例5　使用有人類小細胞肺癌株之聯苯化合物與其他抗腫瘤劑的組合(in vitro)各試劑之獲取來源、腫瘤細胞株之獲取來源、使用培養基、細胞播種數顯示於下表。Test Example 5" Combination of biphenyl compound of human small cell lung cancer strain and other antitumor agents (in vitro) The source of each reagent, the source of tumor cell lines, the medium used, and the number of cell seedings are shown in the table below.

[表85]

Figure 107117996-A0304-0040
[Table 85]
Figure 107117996-A0304-0040

[表86]

Figure 107117996-A0304-0041
[Table 86]
Figure 107117996-A0304-0041

細胞是以100μL/孔來播種到96孔培養盤(NUNC)。將播種好細胞之盤在已設定為37℃、5% CO2的培養器内培養。播種隔日，將已混合各種濃度組合之聯苯化合物與其他具有抗腫瘤效果之化合物的藥液添加至細胞。詳細來說，使用含有10% FBS之RPMI-1640培養基，或含有10%FBS之F-12K培養基，針對聯苯化合物(實施例化合物37、166、177、273)是調製8階段的系列稀釋液(包含0nM)，針對其他具有抗腫瘤效果之化合物亦是調製8階段之系列稀釋液(包含0nM)。將已等量分注各化合物系列稀釋液的藥液以1比1之比來混合，調製出全部組合計共64種的混合藥液。下表顯示各藥劑之最高濃度(以最終濃度表示)及公比。將該混合藥液以100μL/孔(N＝1)添加到盤中後，進一步以37℃、5% CO2 的條件培養10天。10天後，從各孔移除培養上清液100μL，以殘留100μL之細胞培養液。對殘留之細胞培養液100μL，添加CellTiter-Glo　2.0　Assay(Promega、Cat＃：G9242) 100μL/孔。化學發光之測定是與試驗例4相同。Cells are seeded into 96-well culture plates (NUNC) at 100 μL/well. The seeded cells are cultured in an incubator set at 37°C and 5% CO2. On the second day of sowing, add a medicinal solution containing various combinations of biphenyl compounds and other compounds with antitumor effects to the cells. In detail, use RPMI-1640 medium containing 10% FBS or F-12K medium containing 10% FBS. For biphenyl compounds (Example Compounds 37, 166, 177, 273), 8-stage serial dilutions (Including 0 nM), for other compounds with anti-tumor effects, 8 stages of serial dilutions (containing 0 nM) are also prepared. The medicinal solutions in which the serial dilutions of each compound have been dispensed in equal amounts are mixed in a ratio of 1:1 to prepare a mixed medicinal solution of 64 kinds in total in all combinations. The following table shows the highest concentration (expressed as the final concentration) and common ratio of each agent. After this mixed drug solution was added to the dish at 100 μL/well (N=1), it was further cultured under the conditions of 37° C. and 5% CO 2 for 10 days. After 10 days, 100 μL of the culture supernatant was removed from each well to leave 100 μL of the cell culture solution. To 100 μL of the remaining cell culture medium, add 100 μL/well of CellTiter-Glo 2.0 Assay (Promega, Cat#: G9242). The measurement of chemiluminescence is the same as in Test Example 4.

[表87]

Figure 107117996-A0304-0042
[Table 87]
Figure 107117996-A0304-0042

針對藥劑之併用所產生之效果增強，是依記載於習知文獻(Trends　Pharmacol.Sci., 4, 450-454, 1983, Pharmacol Rev., 58(3), 621-81, 2006)之方法為準來評價。具體的方法及併用效果之判定方法是與試驗例4相同。The enhanced effect of the combined use of drugs is based on the method described in the literature (Trends　Pharmacol. Sci., 4, 450-454, 1983, Pharmacol Rev., 58(3), 621-81, 2006). Standard to evaluate. The specific method and the judgment method of the combined effect are the same as those of Test Example 4.

將結果示於下表。The results are shown in the table below.

[表88]

Figure 107117996-A0304-0043
[Table 88]
Figure 107117996-A0304-0043

[表89]

Figure 107117996-A0304-0044
[Table 89]
Figure 107117996-A0304-0044

[表90]

Figure 107117996-A0304-0045
[Table 90]
Figure 107117996-A0304-0045

[表91]

Figure 107117996-A0304-0046
[Table 91]
Figure 107117996-A0304-0046

[表92]

Figure 107117996-A0304-0047
[Table 92]
Figure 107117996-A0304-0047

[表93]

Figure 107117996-A0304-0048
[Table 93]
Figure 107117996-A0304-0048

[表94]

Figure 107117996-A0304-0049
[Table 94]
Figure 107117996-A0304-0049

[表95]

Figure 107117996-A0304-0050
[Table 95]
Figure 107117996-A0304-0050

[表96]

Figure 107117996-A0304-0051
[Table 96]
Figure 107117996-A0304-0051

[表97]

Figure 107117996-A0304-0052
[Table 97]
Figure 107117996-A0304-0052

[表98]

Figure 107117996-A0304-0053
[Table 98]
Figure 107117996-A0304-0053

[表99]

Figure 107117996-A0304-0054
[Table 99]
Figure 107117996-A0304-0054

[表100]

Figure 107117996-A0304-0055
[Table 100]
Figure 107117996-A0304-0055

[表101]

Figure 107117996-A0304-0056
[Table 101]
Figure 107117996-A0304-0056

[表102]

Figure 107117996-A0304-0057
[Table 102]
Figure 107117996-A0304-0057

[表103]

Figure 107117996-A0304-0058
[Table 103]
Figure 107117996-A0304-0058

[表104]

Figure 107117996-A0304-0059
[Table 104]
Figure 107117996-A0304-0059

[表105]

Figure 107117996-A0304-0060
[Table 105]
Figure 107117996-A0304-0060

[表106]

Figure 107117996-A0304-0061
[Table 106]
Figure 107117996-A0304-0061

[表107]

Figure 107117996-A0304-0062
[Table 107]
Figure 107117996-A0304-0062

[表108]

Figure 107117996-A0304-0063
[Table 108]
Figure 107117996-A0304-0063

[表109]

Figure 107117996-A0304-0064
[Table 109]
Figure 107117996-A0304-0064

[表110]

Figure 107117996-A0304-0065
[Table 110]
Figure 107117996-A0304-0065

[表111]

Figure 107117996-A0304-0066
[Table 111]
Figure 107117996-A0304-0066

[表112]

Figure 107117996-A0304-0067
[Table 112]
Figure 107117996-A0304-0067

[表113]

Figure 107117996-A0304-0068
[Table 113]
Figure 107117996-A0304-0068

[表114]

Figure 107117996-A0304-0069
[Table 114]
Figure 107117996-A0304-0069

[表115]

Figure 107117996-A0304-0070
[Table 115]
Figure 107117996-A0304-0070

從該結果顯示出，聯苯化合物透過與鉑系藥劑之順鉑、卡鉑，或植物生物鹼藥劑之SN-38(愛萊諾迪肯之活性代謝物)、依託泊苷、紫杉醇併用，抗腫瘤效果是協同的增強。The results show that the biphenyl compound can be used in combination with platinum-based cisplatin, carboplatin, or plant alkaloid SN-38 (active metabolite of Eleanor Dicken), etoposide, and paclitaxel. The tumor effect is synergistically enhanced.

試驗例6　使用有人類AML細胞株之聯苯化合物與其他抗腫瘤劑的組合(in vitro)各試劑之獲取來源、腫瘤細胞株之獲取來源、使用培養基、細胞播種數顯示於下表。Test Example 6" Combination of biphenyl compound using human AML cell line and other antitumor agents (in vitro) The source of each reagent, the source of tumor cell line, the medium used, and the number of cell seedings are shown in the table below.

[表116]

Figure 107117996-A0304-0071
[Table 116]
Figure 107117996-A0304-0071

[表117]

Figure 107117996-A0304-0072
[Table 117]
Figure 107117996-A0304-0072

細胞是以100μL/孔來播種到96孔培養盤(NUNC)。將播種好細胞之盤在已設定為37℃、5% CO2的培養器内培養。播種當日，將已混合各種濃度組合之聯苯化合物與其他具有抗腫瘤效果之化合物的藥液添加至細胞。詳細來說，使用含有10% FBS之RPMI-1640培養基，針對聯苯化合物(實施例化合物37、166、177、273)是調製8階段的系列稀釋液(包含0nM)，針對其他具有抗腫瘤效果之化合物亦是調製8階段之系列稀釋液(包含0nM)。下表顯示各藥劑之最高濃度(以最終濃度表示)及公比。Cells are seeded into 96-well culture plates (NUNC) at 100 μL/well. The seeded cells are cultured in an incubator set at 37°C and 5% CO2. On the day of planting, add a medicinal solution containing various combinations of biphenyl compounds and other compounds with anti-tumor effects to the cells. In detail, using RPMI-1640 medium containing 10% FBS, for biphenyl compounds (Example Compounds 37, 166, 177, and 273), 8-stage serial dilutions (including 0 nM) were prepared, which had anti-tumor effects against others. The compound is also prepared in 8-stage serial dilutions (including 0 nM). The following table shows the highest concentration (expressed as the final concentration) and common ratio of each agent.

關於系列稀釋液之製作以後的作業，是與試驗例5相同。The work after preparation of the serial dilution liquid is the same as in Test Example 5.

[表118]

Figure 107117996-A0304-0073
[Table 118]
Figure 107117996-A0304-0073

針對藥劑之併用所產生之效果增強，是依記載於習知文獻(Trends　Pharmacol.Sci., 4, 450-454, 1983, Pharmacol Rev., 58(3), 621-81, 2006)之方法為準來評價。具體的方法及併用效果之判定方法是與試驗例4相同。The enhanced effect of the combined use of drugs is based on the method described in the literature (Trends　Pharmacol. Sci., 4, 450-454, 1983, Pharmacol Rev., 58(3), 621-81, 2006). Standard to evaluate. The specific method and the judgment method of the combined effect are the same as those of Test Example 4.

結果顯示於下表。The results are shown in the table below.

[表119]

Figure 107117996-A0304-0074
[Table 119]
Figure 107117996-A0304-0074

[表120]

Figure 107117996-A0304-0075
[Table 120]
Figure 107117996-A0304-0075

[表121]

Figure 107117996-A0304-0076
[Table 121]
Figure 107117996-A0304-0076

[表122]

Figure 107117996-A0304-0077
[Table 122]
Figure 107117996-A0304-0077

[表123]

Figure 107117996-A0304-0078
[Table 123]
Figure 107117996-A0304-0078

[表124]

Figure 107117996-A0304-0079
[Table 124]
Figure 107117996-A0304-0079

[表125]

Figure 107117996-A0304-0080
[Table 125]
Figure 107117996-A0304-0080

[表126]

Figure 107117996-A0304-0081
[Table 126]
Figure 107117996-A0304-0081

從該結果顯示出，聯苯化合物透過與人類MDM2(HDM2)抑制劑之RG7388、或DNA甲基化抑制劑之鳥地西他濱併用，抗腫瘤效果會協同的增強。The results show that the anti-tumor effect of biphenyl compound can be synergistically enhanced by using RG7388, which is an inhibitor of human MDM2 (HDM2), or avian decitabine, which is an inhibitor of DNA methylation, to synergistically increase its anti-tumor effect.

如上，通式(I)表示的聯苯化合物在與各種其他抗腫瘤劑組合時，顯示出使抗腫瘤效果增強的效果。As above, the biphenyl compound represented by the general formula (I), when combined with various other antitumor agents, exhibits the effect of enhancing the antitumor effect.

Figure 107117996-A0101-11-0002-3
Figure 107117996-A0101-11-0002-3

(無)(no)

Claims (15)

一種抗腫瘤劑，特徵在於併用下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑：
Figure 107117996-A0305-02-0378-1
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具 有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 An antitumor agent characterized by using a biphenyl compound represented by the following general formula (I) or a salt thereof in combination with other antitumor agents:
Figure 107117996-A0305-02-0378-1
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 如請求項1之抗腫瘤劑，其中聯苯化合物在通式(I)中滿足下述條件：環A為吡咯啶基、哌啶基、哌嗪基、吖
Figure 107117996-A0305-02-0380-11
基(azepanyl group)、二吖
Figure 107117996-A0305-02-0380-12
基(diazepanyl group)、
Figure 107117996-A0305-02-0380-2
 、2,7-二氮雜螺[3.4]辛基、3,7-二氮雜螺[3.4]辛基、2,7-二氮雜螺[3.5]壬基、2,8-二氮雜螺[3.5]壬基、3,7-二氮雜螺[3.5]壬基、3,8-二氮雜螺[4.4]壬基、3,8-二氮雜螺[4.5]癸基，或9-氧雜-二氮雜螺[3.5]壬基，環B為苯基、萘基、吡啶基、吡唑并吡啶基、吡唑并嘧啶基、吲哚基、吲哚啉基、2-側氧基-吲哚啉基、吲唑基、苯并咪唑基、苯并異噁唑基、苯并噻唑基、苯并三唑基、咪唑并吡啶基、喹啉基、異喹啉基、喹噁啉基、喹唑啉基、呔嗪基、2-側氧基-2,3-二氫苯并[d]噁唑基、1,3-二氫異苯并呋喃基、二氫苯并氧氮雜芑基(dihydrobenzoxazinyl)、苯并二噁
Figure 107117996-A0305-02-0380-13
基(benzodioxolyl)、二氫苯并二噁嗪基(dihydrobenzodioxinyl)，或2-側氧基-2,3-二氫苯并[d]噻唑基，R1為硝基或氰基，R2為氟原子， 該R2在苯基上相對於R1存在於鄰位，R3為胺基、甲基胺基、乙基胺基、異丙基胺基、二甲基胺基、環丁基胺基，或甲基；當R3存在有複數個時，該等R3可相同亦可相異，R4為氟原子、氯原子、溴原子、碘原子、硝基、氰基、羧基、甲基、乙基、正丙基、異丙基、第三丁基、二氟甲基、三氟甲基、氟乙基、胺基乙基、羥基甲基、羥基乙基、羥基丙基、羥基二甲基乙基、羥基甲基丙基、羥基甲基丁基、羥基乙基丁基、羧基甲基、胺甲醯基甲基、甲基胺甲醯基甲基、二甲基胺甲醯基甲基、乙醯基胺基乙基、甲氧基乙基、羥基環丙基甲基、羥基環丙基乙基、羥基環丁基甲基、甲基羰基氧基乙基、異丁烯基、甲氧基、羥基丙氧基、環丙基、羥基甲基環丙基、甲氧基甲基環丙基、羥基環丙基環丙基、苯基胺甲醯基環丙基、苯甲基氧基、二甲基胺基、胺甲醯基、甲基胺甲醯基，或二甲基胺甲醯基；當R4存在有複數個時，該等R4可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，n表示0~3之整數，當n為2~3時，2~3個R4可相同亦可相異。 The antitumor agent of claim 1, wherein the biphenyl compound meets the following conditions in the general formula (I): ring A is pyrrolidinyl, piperidinyl, piperazinyl, acridine
Figure 107117996-A0305-02-0380-11
Base (azepanyl group), two acridine
Figure 107117996-A0305-02-0380-12
Base (diazepanyl group),
Figure 107117996-A0305-02-0380-2
 , 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazepine Spiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, ring B is phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indolinyl, 2- Pendant oxy-indolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolinyl, isoquinolinyl, Quinoxolinyl, quinazolinyl, oxazinyl, 2-side oxy-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzene Dihydrobenzoxazinyl, benzodioxin
Figure 107117996-A0305-02-0380-13
Group (benzodioxolyl), dihydrobenzodioxinyl (dihydrobenzodioxinyl), or 2-side oxy-2,3-dihydrobenzo[d]thiazolyl, R1 is nitro or cyano, R2 is fluorine atom , The R2 exists in the ortho position relative to R1 on the phenyl group, and R3 is an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, a cyclobutylamino group, or a methyl group. Group; when there are plural R3, these R3 may be the same or different, R4 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, a n-propyl group Base, isopropyl, tertiary butyl, difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxy Methyl propyl, hydroxymethyl butyl, hydroxyethyl butyl, carboxymethyl, carbamate methyl, methyl carbamate methyl, dimethyl carbamate, acetyl Aminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutenyl, methoxy, hydroxypropoxy, Cyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, phenylaminomethylcyclopropyl, benzyloxy, dimethylamino, Carboxamide, methylcarboxamide, or dimethylcarboxamide; when there are more than one R4, these R4 can be the same or different, and R5 and R6 can be the same or different, representing a hydrogen atom Or C1-C6 alkyl, or R5 and R6 together form a pendant oxy or thioketo group. When R5 and R6 are the same or different and represent a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 1 is a hydrogen atom, n represents an integer from 0 to 3, when n is 2 to 3, 2 to 3 R4 can be the same or different. 如請求項1或2之抗腫瘤劑，其中聯苯化合物係選自於以下(1)~(7)者： (1)4-[5-[(3S)-3-胺基吡咯啶-1-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈、(2)4-[5-[(3-內)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羰基]-2-[2-氟-4-(2-羥基-2-甲基-丙基)苯基]苯基]-2-氟-苯甲腈、(3)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2”,3-二氟-4”-(2-羥基-2-甲基丙基)-[1,1’：2’,1”-聯三苯]-4-甲腈-異構物-B、(4)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-B、(5)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(1-(2-乙基-2-羥基丁基)-6,7-二氟-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X、(6)5’-((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-羰基)-2’-(7-溴-6-氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X、(7)5’-(((1S,2S,4R)-rel-2-胺基-7-氮雜雙環[2.2.1]庚烷-7-基)甲基)-2’-(6,7-二氟-1-(2-羥基-2-甲基丙基)-1H-苯并[d][1,2,3]三唑-5-基)-3-氟-[1,1’-聯苯]-4-甲腈-異構物-X。 The anti-tumor agent of claim 1 or 2, wherein the biphenyl compound is selected from the following (1) to (7): (1) 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl] Phenyl]-2-fluoro-benzonitrile, (2)4-[5-[(3-internal)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]- 2-[2-Fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile, (3)5'-((1S,2S,4R )-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2",3-difluoro-4"-(2-hydroxy-2-methylpropyl) -[1,1': 2',1”-terphenyl]-4-carbonitrile-isomer-B, (4)5'-((1S,2S,4R)-rel-2-amino -7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[ d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B, (5)5'-(( 1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl) -6,7-Difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-iso Structure-X, (6)5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7 -Bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1 ,1'-Biphenyl]-4-carbonitrile-isomer-X, (7)5'-(((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2. 1]Heptane-7-yl)methyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2 ,3]Triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X. 如請求項1或2之抗腫瘤劑，其中其他抗腫瘤劑為選自於代謝拮抗劑、抗腫瘤性抗生素、分子標的藥、鉑系藥劑、及植物生物鹼藥劑中之至少1種以上。 The anti-tumor agent of claim 1 or 2, wherein the other anti-tumor agent is at least one or more selected from the group consisting of metabolic antagonists, anti-tumor antibiotics, molecular target drugs, platinum-based drugs, and plant alkaloid drugs. 如請求項3之抗腫瘤劑，其中其他抗腫瘤劑為選自於代謝拮抗劑、抗腫瘤性抗生素、分子標的藥、鉑系藥劑、及植物生物鹼藥劑中之至少1種以上。 The antitumor agent of claim 3, wherein the other antitumor agent is at least one or more selected from the group consisting of metabolic antagonists, antitumor antibiotics, molecular target drugs, platinum-based drugs, and plant alkaloid drugs. 如請求項1或2之抗腫瘤劑，其中其他抗腫瘤劑為選自於阿糖胞苷、氮雜胞苷、地西他濱、鳥地西他濱、道諾黴素、維A酸(ATRA)、RG7388、卡鉑、順鉑、紫杉醇、愛萊諾迪肯(SN-38)、及依託泊苷中之至少1種以上。 The anti-tumor agent of claim 1 or 2, wherein the other anti-tumor agent is selected from the group consisting of cytarabine, azacytidine, decitabine, guandecitabine, daunorubicin, tretinoin ( At least one of ATRA), RG7388, carboplatin, cisplatin, paclitaxel, Eleanor Dicken (SN-38), and etoposide. 請求項3之抗腫瘤劑，其中其他抗腫瘤劑為選自於阿糖胞苷、氮雜胞苷、地西他濱、鳥地西他濱、道諾黴素、維A酸(ATRA)、RG7388、卡鉑、順鉑、紫杉醇、愛萊諾迪肯(SN-38)、及依託泊苷中之至少1種以上 The antitumor agent of claim 3, wherein the other antitumor agent is selected from the group consisting of cytarabine, azacytidine, decitabine, guandecitabine, daunorubicin, tretinoin (ATRA), At least one of RG7388, carboplatin, cisplatin, paclitaxel, Eleanor Dicken (SN-38), and etoposide 一種抗腫瘤劑，係組合聯苯化合物或其鹽、與其他抗腫瘤劑而成者，聯苯化合物為下述通式(I)表示的化合物：[化學式3]
Figure 107117996-A0305-02-0384-3
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代 基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 An antitumor agent, which is a combination of a biphenyl compound or its salt and other antitumor agents. The biphenyl compound is a compound represented by the following general formula (I): [Chemical formula 3]
Figure 107117996-A0305-02-0384-3
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種用於預防及/或治療腫瘤之醫藥組成物，含有以下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑：[化學式4]
Figure 107117996-A0305-02-0386-4
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代 基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A medical composition for preventing and/or treating tumors, containing a biphenyl compound represented by the following general formula (I) or a salt thereof, and other antitumor agents: [Chemical formula 4]
Figure 107117996-A0305-02-0386-4
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種以下述通式(I)表示的聯苯化合物或其鹽之用途，係用以製造其他抗腫瘤劑之抗腫瘤效果增強劑者：[化學式5]
Figure 107117996-A0305-02-0388-5
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代 基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A use of a biphenyl compound represented by the following general formula (I) or a salt thereof to produce an antitumor effect enhancer of other antitumor agents: [Chemical formula 5]
Figure 107117996-A0305-02-0388-5
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種下述通式(I)表示的聯苯化合物或其鹽、與其他抗腫瘤劑之組合之用途，係用以製造一在患者上用以治療及/或預防腫瘤之醫藥：[化學式6]
Figure 107117996-A0305-02-0390-6
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代 基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A use of a biphenyl compound represented by the following general formula (I) or its salt in combination with other antitumor agents is used to manufacture a medicine for treating and/or preventing tumors in patients: [Chemical formula 6]
Figure 107117996-A0305-02-0390-6
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種下述通式(I)表示的聯苯化合物或其鹽之用途，係用以製造一在癌症患者上用以治療及/或預防腫瘤之醫藥，且該癌症患者已投予其他抗腫瘤劑：[化學式7]
Figure 107117996-A0305-02-0392-7
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代 基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A use of a biphenyl compound represented by the following general formula (I) or a salt thereof is used to manufacture a medicine for treating and/or preventing tumors in cancer patients, and the cancer patients have been administered other anti-tumor agents ：[Chemical formula 7]
Figure 107117996-A0305-02-0392-7
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種下述通式(I)表示的聯苯化合物或其鹽之用途，係用以製造一在癌症患者上用以治療及/或預防腫瘤之抗腫瘤效果增強劑，且該癌症患者已投予其他抗腫瘤劑：
Figure 107117996-A0305-02-0394-8
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基， 當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A use of the biphenyl compound represented by the following general formula (I) or its salt is to produce an anti-tumor effect enhancer for treating and/or preventing tumors in cancer patients, and the cancer patients have been administered Other anti-tumor agents:
Figure 107117996-A0305-02-0394-8
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種含有聯苯化合物或其鹽與其他抗腫瘤劑之製品，其係作為一組合製劑，且該組合製劑在用來預防及/或治療腫瘤時，是同時、逐次、或隔著間隔來使 用，聯苯化合物為下述通式(I)表示的聯苯化合物：
Figure 107117996-A0305-02-0396-9
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷 基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A product containing a biphenyl compound or its salt and other antitumor agents, which is used as a combined preparation, and when the combined preparation is used to prevent and/or treat tumors, it is used simultaneously, successively, or at intervals, The biphenyl compound is a biphenyl compound represented by the following general formula (I):
Figure 107117996-A0305-02-0396-9
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ]. 一種以下述通式(I)表示的聯苯化合物或 其鹽與其他抗腫瘤劑之組合：
Figure 107117996-A0305-02-0398-10
 [式中，環A表示單環、橋聯環或螺環的4~14員環之含氮飽和雜環基，其具有1~3個氮原子、0~1個硫原子及0~2個氧原子來作為雜原子，環B表示單環或二環的5~14員環之不飽和烴基；或是單環或二環的5~14員環之不飽和雜環基，其亦可經側氧基取代，且具有0~4個氮原子、0~2個硫原子及0~3個氧原子來作為雜原子，並具有至少1個之氮原子、硫原子及氧原子中任一者，R1表示硝基或氰基，R2表示鹵素原子，R3表示胺基、單或二(C1-C6烷基)胺基、(C3-C7環烷基)胺基，或C1-C6烷基，R4表示鹵素原子、硝基、氰基、羧基、亦可具有取代基的C1-C8烷基、亦可具有取代基的C2-C6烯基、亦可具有取代基的C1-C6烷氧基、亦可具有取代基的C3-C7環烷基、單或二(C1-C6烷基)胺基，或亦可具有取代基的胺甲 醯基，當至少1個R4為具有取代基的C1-C8烷基、具有取代基的C2-C6烯基、具有取代基的C1-C6烷氧基、具有取代基的C3-C7環烷基或具有取代基的胺甲醯基時，該取代基表示鹵素原子、羧基、C1-C6烷氧基、羥基、亦可具有羥基作為取代基之C1-C6烷基、單環且為5~10員環的不飽和烴基、亦可具有C1-C6烷基或是單環且為5~10員環的不飽和烴基作為取代基之胺甲醯基、(C2-C7醯基)氧基、亦可具有C1-C6烷基或C2-C7醯基作為取代基之胺基、亦可具有羥基作為取代基之C3-C7環烷基，或(C1-C6烷氧基)(C1-C6烷基)基團，當該取代基存在有複數個時，其等可相同亦可相異，R5及R6相同或相異，表示氫原子或C1-C6烷基，又或者亦可R5與R6一起形成側氧基或硫酮基，當R5及R6相同或相異，表示氫原子或C1-C6烷基時，R5、R6中之至少1者為氫原子，l表示0~2之整數，m表示0~2之整數，n表示0~5之整數，當l為2時，2個R2可相同亦可相異，當m為2時，2個R3可相同亦可相異，當n為2~5時，2~5個R4可相同亦可相異]。 A combination of a biphenyl compound represented by the following general formula (I) or a salt thereof and other antitumor agents:
Figure 107117996-A0305-02-0398-10
 [In the formula, ring A represents a 4- to 14-membered nitrogen-containing saturated heterocyclic group of monocyclic, bridged ring or spiro ring, which has 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 An oxygen atom is used as a heteroatom. Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group of 5 to 14 members; or a monocyclic or bicyclic unsaturated heterocyclic group of 5 to 14 members, which can also be Pendant oxy groups are substituted, and have 0~4 nitrogen atoms, 0~2 sulfur atoms and 0~3 oxygen atoms as heteroatoms, and have at least one of nitrogen, sulfur and oxygen atoms , R1 represents a nitro group or a cyano group, R2 represents a halogen atom, R3 represents an amino group, a mono or di(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group, or a C1-C6 alkyl group, R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C8 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, It may also have a substituted C3-C7 cycloalkyl group, a mono- or di(C1-C6 alkyl)amino group, or a substituted aminomethyl group, when at least one R4 is a substituted C1- In the case of a C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted aminomethyl group, the substituent represents Halogen atom, carboxyl group, C1-C6 alkoxy group, hydroxyl group, C1-C6 alkyl group which may also have a hydroxyl group as a substituent, monocyclic and unsaturated hydrocarbon group of 5-10 members, and may also have C1-C6 alkyl group Or monocyclic and 5- to 10-membered unsaturated hydrocarbon group as substituent amine methanyl, (C2-C7 acyl)oxy group, can also have C1-C6 alkyl or C2-C7 acyl as substituent The amino group of the group, the C3-C7 cycloalkyl group or (C1-C6 alkoxy) (C1-C6 alkyl) group that may also have a hydroxyl group as a substituent, when there are plural substituents, it R5 and R6 can be the same or different. R5 and R6 are the same or different. They represent a hydrogen atom or a C1-C6 alkyl group, or R5 and R6 can form a pendant oxy or thioketo group together. When R5 and R6 are the same or are the same Iso, when it represents a hydrogen atom or a C1-C6 alkyl group, at least one of R5 and R6 is a hydrogen atom, l represents an integer from 0 to 2, m represents an integer from 0 to 2, and n represents an integer from 0 to 5. When l is 2, two R2s can be the same or different. When m is 2, two R3s can be the same or different. When n is 2~5, 2~5 R4s can be the same or different. ].
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